Treatment selection for personalized lymphoma treatment

Abstract

The present disclosure provides methods and kits for obtaining sequence information of one or more genes from a subject diagnosed with a disease or disorder. Based on the sequence information, the present disclosure further provides methods of predicting a treatment outcome of the subject.

Description

Attorney Ref: 42800-64265 / WO (001WO)TREATMENT SELECTION FOR PERSONALIZED LYMPHOMA TREATMENT1. CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to US Provisional Application No. 63 / 690,279, filed September 3, 2024, the disclosure of which is incorporated by reference in its entirety.2. BACKGROUND OF THE INVENTION

[0002] Leukemia and Lymphoma originate in lymphocytes of an individual. Leukemia and lymphoma are characterized by genetic heterogenicity, resulting in different phenotypic disease presentations as well as clinical responses to different therapies in diagnosed individuals. In 2023, over 83,000 new cases of leukemia and lymphoma were diagnosed and over 110,000 leukemia and lymphoma patients died. There is a need to develop a way to diagnose and identify optimal treatment options for patients to achieve better therapeutic outcomes.3. SUMMARY OF THE INVENTION

[0003] Blood-based cancers, such as leukemia and lymphoma, can be difficult to treat due to the systemic nature of the cancer and the heterogenicity of cancer cells in each patient. The implementation of personalized treatment regimens can increase the likelihood of success of initial treatments in diseases, such as blood-based cancers, and therefore increase the quality of life of the patients. The present invention utilizes genetic information specific to a subject diagnosed with a disease to predict treatment outcomes of various therapies.

[0004] One aspect of the present disclosure provides a method for treating a subject with lymphoma, comprising: a) obtaining sequence information of one or more genes in the subject, wherein the one or more genes comprise: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSC AFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and / or mammalian orthologs thereof, b) based on the sequence information, predicting a treatment outcome of the subject, and c) providing information related to the prediction to (i) the subject or (ii) a care giver or a medical provider for the subject for use in treatment of the subject.

[0005] In some embodiments, the one or more additional genes are selected from KMT2C,KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2,Attorney Ref: 42800-64265 / WO (001WO)CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0006] In some embodiments, the method further comprises: d) selecting a treatment regiment based on the prediction. In some embodiments, the method further comprises: e) causing to treat the subject by the selected treatment regimen.

[0007] In some embodiments of any one of the preceding embodiments, the method further comprises: a preceding step of generating the sequence information by analyzing a sample of the subject. In some embodiments, the step of generating the sequence information comprises contacting the sample with one or more probes, thereby inducing hybridization of one or more target polynucleotides in the sample with the one or more probes. In some embodiments, each of the one or more probes is configured to bind to a sequence specific to the one or more genes. In some embodiments, each of the one or more target polynucleotides comprises the sequence specific to the one or more genes. In some embodiments, the one or more target polynucleotides comprises one or more mutations. In some embodiments, the step of generating the sequence information further comprises enriching the one or more target polynucleotides hybridized with the one or more probes from the sample. In some embodiments, the enriching step is performed by reacting the one or more probes with a bead and isolating the bead, thereby obtaining enriched target polynucleotides, wherein the bead is configured to bind to the one or more probes. In some embodiments, the bead is a magnetic streptavidin bead.

[0008] In some embodiments of any one of the preceding embodiments, the step of generating the sequence information further comprises amplifying the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides. In some embodiments, the one or more target polynucleotides or the enriched polynucleotides are amplified via a polymerase. In some embodiments, the polymerase is an RNA polymerase or a DNA polymerase.

[0009] In some embodiments of any one of the preceding embodiments, the step of generating the sequence information further comprises sequencing (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, or (iii) enriched and amplified target polynucleotides. In some embodiments,Attorney Ref: 42800-64265 / WO (001WO) the sequencing is performed by next generation sequencing. In some embodiments, the step of sequencing further comprises identifying one or more mutations in the one or more genes.

[0010] In some embodiments, the step of generating the sequence information comprises contacting the sample with one or more pairs of primers, thereby inducing hybridization of one or more target polynucleotides in the sample with the one or more pairs of primers. In some embodiments, each of the one or more pairs of primers is configured to bind to a sequence specific to the one or more genes. In some embodiments, each of the one or more target polynucleotides comprises the sequence specific to the one or more genes. In some embodiments, the step of generating the sequence information further comprises amplifying the one or more target polynucleotides hybridized with the one or more pairs of primers. In some embodiments, the one or more primers are extended via a polymerase. In some embodiments, the polymerase is an RNA polymerase or a DNA polymerase. In some embodiments, the polymerase extends the one or more pairs of primers using the one or more target polynucleotides as a template. In some embodiments of any one of the preceding embodiments, the amplifying step comprises performing polymerase chain reaction (PCR) or quantitative PCR. In some embodiments of any one of the preceding embodiments, the amplifying step comprises quantitative PCR (qPCR). In some embodiments, the qPCR is performed in the presence of a mutant-specific probe configured to bind to one of the target polynucleotides with a mutation. In some embodiments, the mutant-specific probe is labeled with a fluorescent dye and a quencher. In some embodiments, the qPCR is performed in the presence of a control probe configured to bind to one of the target polynucleotides without the mutation. In some embodiments, the control probe is labeled with a different fluorescent dye and a different quencher. In some embodiments of any one of the preceding embodiments, the method further comprises detecting fluorescent signals from the mutantspecific probe and / or the control probe, thereby determining presence, absence or relative abundance of the mutation in the one of the target polynucleotide.

[0011] In some embodiments of any one of the preceding embodiments, the step of generating the sequence information further comprises sequencing the amplified target polynucleotides. In some embodiments, the sequencing is performed by next generation sequencing. In some embodiments, the step of sequencing further comprises identifying one or more mutations in the one or more genes.Attorney Ref: 42800-64265 / WO (001WO)

[0012] In some embodiments of any one of the preceding embodiments, the amplified target polynucleotides comprise the one or more mutations in the one or more genes. In some embodiments, each of the one or more pairs of primers is configured to amplify the one or more target polynucleotides that comprise the one or more mutations.

[0013] In some embodiments of any one of the preceding embodiments, the one or more genes are 20 different genes, 19 different genes, 18 different genes, 17 different genes, 16 different genes, 15 different genes, 14 different genes, 13 different genes, 12 different genes, 11 different genes, 10 , 9 different genes, 8 different genes, 7 different genes, 6 different genes, 5 different genes, 4 different genes, 3 different genes, 2 different genes or a single gene selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1 , ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1 , TNFRSF1 1A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0014] In some embodiments of any one of the preceding embodiments, the one or more genes are the first 20 genes, the first 19 genes, the first 18 genes, the first 17 genes, the first 16 genes, the first 15 genes, the first 14 genes, the first 13 genes, the first 12 genes, the first 11 genes, the first 10 genes, the first 9 genes, the first 8 genes, the first 7 genes, the first 6 genes, the first 5 genes, the first 4 genes, the first 3 genes, or the first 2 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs.

[0015] In some embodiments of any one of the preceding embodiments, the one or more genes are KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, and TP53, or mammalian orthologs thereof.

[0016] In some embodiments of any one of the preceding embodiments, the one or more genes are PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof. In some embodiments, the subject has T-cell lymphomas (TCLs).

[0017] In some embodiments of any one of the preceding embodiments, the one or more genes are FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof. In some embodiments, the subject has B-cell lymphomas (BCLs).Attorney Ref: 42800-64265 / WO (001WO)

[0018] In some embodiments of any one of the preceding embodiments, the one or more genes are TRAF3 and FBXW7, or mammalian orthologs thereof.

[0019] In some embodiments of any one of the preceding embodiments, the one or more genes are TRAF3 and KMT2D, or mammalian orthologs thereof.

[0020] In some embodiments of any one of the preceding embodiments, the one or more genes are PIK3CD and CREBBP, or mammalian orthologs thereof.

[0021] In some embodiments of any one of the preceding embodiments, the one or more genes are CREBBP or a mammalian ortholog thereof.

[0022] In some embodiments of any one of the preceding embodiments, the one or more genes are TRAF3 or a mammalian ortholog thereof.

[0023] In some embodiments of any one of the preceding embodiments, the one or more genes are FBXW7 or a mammalian ortholog thereof.

[0024] In some embodiments of any one of the preceding embodiments, the one or more genes are CCND1 or a mammalian ortholog thereof.

[0025] In some embodiments of any one of the preceding embodiments, the one or more genes are KMT2C or a mammalian ortholog thereof.

[0026] In some embodiments of any one of the preceding embodiments, the one or more genes are NOTCH2 or a mammalian ortholog thereof.

[0027] In some embodiments of any one of the preceding embodiments, the one or more genes are PIK3CD or a mammalian ortholog thereof.

[0028] In some embodiments of any one of the preceding embodiments, the one or more genes are selected from SETD2, TP53, and TRAF3, or mammalian orthologs thereof.

[0029] In some embodiments of any one of the preceding embodiments, the one or more genes are selected from a-d, wherein a-d are: a) KMT2C and NOTCH2, or mammalian orthologs thereof, b) KMT2D and KMT2C, or mammalian orthologs thereof, c) KMT2C and BCL1 IB, or mammalian orthologs thereof, or d) KMT2D and NOTCH2, or mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (001WO)

[0030] In some embodiments of any one of the preceding embodiments, the one or more genes are selected from a-e, wherein a-e are: a) TRAF3 and SETD2 or mammalian orthologs thereof, b) TRAF3 and POTI, or mammalian orthologs thereof, c) TRAF3 and TBL1XR1, or mammalian orthologs thereof, d) TP53 and SETD2, or mammalian orthologs thereof, or e) POTI and FBXW7, or mammalian orthologs thereof.

[0031] In some embodiments of any one of the preceding embodiments, the one or more genes are selected from a-j, wherein a-j are: a) MTOR, KLF4, VEGFA or mammalian orthologs thereof, b) MTOR, KLF4, ITK or mammalian orthologs thereof, c) CCND1, KMT2D, TP53, ARID1A or mammalian orthologs thereof, d) CCND1, TNFRSF11A, SLC19A1, TP53 or mammalian orthologs thereof, e) CCND1, TP53 or mammalian orthologs thereof, f) TP53, SETD2, SLC7A5 or mammalian orthologs thereof, g) GNA13, TP53, ENSCAFG00000001448 or mammalian orthologs thereof, h) EP3000, ABCC5, FOXL2 or mammalian orthologs thereof, i) PIK3CD, CREBBP, FBXW7, TRAF3 or mammalian orthologs thereof, or j) NOTCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, KMT2D or mammalian orthologs thereof.

[0032] In some embodiments of any one of the preceding embodiments, the treatment regimen is selected from the group consisting of: chemotherapy, immunotherapy, radiation, hormone therapy, surgery, bone marrow transplant, and any combination thereof. In some embodiments, the chemotherapy is selected from the group consisting of: a cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) regimen, a L-asparaginase CHOP (L-CHOP) regimen, a rituximab CHOP (R-CHOP) regimen, a lomustine (CCNU) regimen, a rabacfocsadine regimen, a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen, and any combination thereof.

[0033] In some embodiments of any one of the preceding embodiments, in step c), a positive response to a CHOP regimen or a L-CHOP regimen is predicted when (i) the subject has mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has B-cell lymphoma (BCL). In some embodiments of any one of the preceding embodiments, in step d), a CHOP regimen or a L-CHOP regimen is selected when (i) the subject has mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has B-cell lymphoma (BCL).Attorney Ref: 42800-64265 / WO (001WO)

[0034] In some embodiments of any one of the preceding embodiments, in step c), a positive response to a CHOP regimen or a L-CHOP regimen is predicted when the subject has a mutation in TRAF3 or a mammalian ortholog thereof. In some embodiments of any one of the preceding embodiments, in step d), a CHOP regimen or a L-CHOP regimen is selected when the subject has a mutation in TRAF3 or a mammalian ortholog thereof. In some embodiments, the mutation or the mutations in TRAF3 comprise C.1267C>T. In some embodiments, the mutation or the mutations in TRAF3 are located in a domain for trimerization of TRAF3.

[0035] In some embodiments of any one of the preceding embodiments, in step c), a positive response to a CHOP regimen or a Tanovea-based regimen is predicted when (i) the subject has B-cell lymphoma (BCL) and (ii) has a mutation in TRAF3, KMT2D, or both, or mammalian orthologs thereof. In some embodiments of any one of the preceding embodiments, in step d), a CHOP regimen or a Tanovea-based regimen is selected when the subject has (i) B-cell lymphoma (BCL) and (ii) a mutation in TRAF3, KMT2D, or both, or mammalian orthologs thereof.

[0036] In some embodiments of any one of the preceding embodiments, in step c), a negative response to a CHOP regimen is predicted when the subject has (i) B-cell lymphoma (BCLs) and (ii) a mutation in CCND 1 or a mammalian ortholog thereof. In some embodiments of any one of the preceding embodiments, in step d), a CHOP regimen is not selected when the subject has (i) B-cell lymphoma (BCL) and (ii) a mutation in CCND1 or a mammalian ortholog thereof.

[0037] In some embodiments of any one of the preceding embodiments, in step c), a negative response to a CHOP-like regimen, a lomustine-containing regimen, or both is predicted when (i) the subject has T-cell lymphoma (TCL) and (ii) has a mutation in PIK3D, CREBBP, or both, or mammalian orthologs thereof. In some embodiments of any one of the preceding embodiments, in step d), a CHOP-like regimen, a lomustine-containing regimen, or both is not selected when (i) the subject has T-cell lymphoma (TCL) and (ii) has a mutation in PIK3D, CREBBP, or both, or mammalian orthologs thereof.

[0038] In some embodiments of any one of the preceding embodiments, in step c), a positive response to a CHOP regimen is predicted when the subject has (i) T-cell lymphoma (TCL) and (ii) a mutation in KMT2C, NOTCH2 or both, or mammalian orthologs thereof. In someAttorney Ref: 42800-64265 / WO (001WO) embodiments of any one of the preceding embodiments, in step d), a CHOP regimen is selected when the subject has (i) T-cell lymphoma (TCL) and (ii) a mutation in KMT2C, N0TCH2 or both, or mammalian orthologs thereof.

[0039] In some embodiments of any one of the preceding embodiments, in step c), a negative response to a first line therapy is predicted when the subject has a mutation in TP53, or a mammalian ortholog thereof.

[0040] In some embodiments of any one of the preceding embodiments, the mutation or the mutations are somatic mutations, germline mutations, or both.

[0041] In some embodiments of any one of the preceding embodiments, in step b), predicting the treatment outcome of the subject comprises: extracting features related to one or more mutations in the one or more genes, the one or more genes comprise MTOR, KLF4, VEGFA or mammalian orthologs thereof and the treatment regimen comprises doxorubicin hydrochloride inputting the features into a machine learning model to assign the subject to one of a plurality of clusters, wherein each cluster represents a mutational profile of a plurality of other subjects and their treatment outcome, and predicting, using the classified cluster or a random forest, the treatment outcome. In some embodiments, a) the one or more genes comprise MTOR, KLF4, VEGFA or mammalian orthologs thereof and the treatment regimen comprises doxorubicin hydrochloride, b) the one or more genes comprise MTOR, KLF4, ITK or mammalian orthologs thereof and the treatment regimen comprises doxorubicin hydrochloride, c) the one or more genes comprise CCND1, KMT2D, TP53, ARID 1 A or mammalian orthologs thereof and the treatment regimen comprises a tanovea- based regimen, d) the one or more genes comprise CCND1 , TNFRSF11A, SLC19A1, TP53 or mammalian orthologs and the treatment regimen comprises a tanovea-based regimen, e) the one or more genes comprise CCND1, TP53 or mammalian orthologs and the treatment regimen comprises a tanovea-based regimen, f) the one or more genes comprise TP53, SETD2, SLC7A5 or mammalian orthologs and the treatment regimen comprises CCNU, g) the one or more genes comprise TP53, SETD2, SLC7A5 or mammalian orthologs and the treatment regimen comprises CCNU, h) the one or more genes comprise GNA13, TP53, ENSCAFG00000001448 or mammalian orthologs and the treatment regimen comprises CCNU, i) the one or more genes comprise EP3000, ABCC5, FOXL2 or mammalian orthologs and the treatment regimen comprises CCNU, j) the one or more genes comprise EP3000, ABCC5, FOXL2 or mammalian orthologs and the treatment regimen comprisesAttorney Ref: 42800-64265 / WO (001WO)CCNU, k) the one or more genes comprise PIK3CD, CREBBP, FBXW7, TRAF3 or mammalian orthologs and the treatment regimen comprises CHOP, or 1) the one or more genes comprise N0TCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, and KMT2D or mammalian orthologs and the treatment regimen comprises CHOP.

[0042] In some embodiments, the machine learning model is an unsupervised model. In some embodiments, the machine learning model is a K-means clustering model, a K-nearest neighbors (KNN) model, a hierarchical clustering model, or a Markov model.

[0043] In some embodiments, the step of extracting features related to one or more mutations comprises: determining co-occurrence of mutations in a pair among the one or more genes, determining an odds ratio for the pair in the one or more genes; and / or providing the cooccurrence or the odds ratios as the features related to the one or more mutations.

[0044] In some embodiments, the step of inputting the features into the machine learning model comprises: applying a clustering algorithm to the features that include the cooccurrence of mutations and the odds ratio to assign the subject into one of the clusters.

[0045] In some embodiments, the machine learning model is a K-means clustering model, generated by the process comprising: selecting a set of candidate genes, retrieving a set of training samples, each training sample comprises mutation information in the candidate genes of training subjects and treatment outcomes of the training subjects, applying a K-means clustering algorithm to the training samples to divide the training samples into a plurality of clusters based on the mutation information in the candidate genes and the treatment outcomes, and determining a quality of the clusters based on treatment outcomes of separate clusters. In some embodiments, the process further comprises: repeating the preceding steps of selecting, retrieving, applying and determining for a set of different candidate genes, and selecting a final set of genes based on the quality of the clusters corresponding to the multiple sets of candidate genes. In some embodiments, the step of determining the quality of the clusters is performed based on whether and / or how well the clusters separate different treatment outcomes based on survival. In some embodiments, the step of determining the quality of the clusters is performed based on a p-value between two or more clusters in predicting the treatment outcomes. In some embodiments, a set of candidate genes that provides a p-value between two or more clusters larger than a threshold is not selected as theAttorney Ref: 42800-64265 / WO (001WO) final set of genes. In some embodiments, the step of determining the quality of the clusters is performed based on a hazard ratio between two or more clusters.

[0046] In some embodiments of any one of the preceding embodiments, the method further comprises: extracting features related to one or more mutations of the subject in a different set of one or more genes that are selected for a different treatment regimen, inputting the features into the machine learning model to assign the subject to one of a plurality of clusters, wherein each cluster represents a mutational profile of a plurality of other subjects and their treatment outcome of the different treatment regimen, predicting, using the classified cluster, the treatment outcome of the different treatment regimen, and selecting a recommended treatment regimen based on the predicted treatment outcomes.

[0047] In some embodiments of any one of the preceding embodiments, the method further comprises: extracting features related to one or more mutations of the subject in a plurality set of one or more genes, wherein each set of one or more genes is selected for one of a plurality of different treatment regimens, inputting the features into the machine learning model to assign the subject to one of a plurality of clusters for each of the plurality of different treatment regimens, wherein each cluster represents a mutational profile of a plurality of other subjects and their treatment outcome of each of the plurality of different treatment regimens, predicting, using the classified cluster, the treatment outcomes for each of the plurality of different treatment regimens, and selecting a recommended treatment regimen based on the predicted treatment outcomes.

[0048] In some embodiments of any one of the preceding embodiments, in step b), additional characteristics of a sample from the subject or the subject is considered for prediction of the treatment outcome. In some embodiments, the additional characteristics comprise an immunophenotype of cells from the subject. In some embodiments, the immunophenotype identifies the cells from the subject as B-cell lymphoma cells. In some embodiments, the immunophenotype identifies the cells from the subject as T-cell lymphoma cells. In some embodiments, the immunophenotype identifies the cells from the subject by expression of one or more surface markers, optionally wherein the surface markers are selected from the group consisting of: CD21, CD20, CD3, CD4, CD8, CD5, and CD45. In some embodiments, the one or more surface markers comprise cell surface receptors or cell surface ligands.Attorney Ref: 42800-64265 / WO (001WO)

[0049] In some embodiments of any one of the preceding embodiments, the additional characteristics comprises ex-vivo drug sensitivity of cells from the subject. In some embodiments, the ex-vivo sensitivity of the cells of the subject is an ex-vivo sensitivity to a drug selected from the group consisting of: Actinomycin D, Docetaxel, Doxorubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Doxycycline, Erythromycin, Itraconazole, Ketoconazole, Levofloxacin, Sparfloxacin, Tetracycline, Amitriptyline, Paroxetine, Venlafaxine, Aldosterone, Cortisol, Dexamethasone, Hydrocortisone, Methylprednisolone, Triamcinolone, Butorphanol, Loperamide, Methadone, Morphine, Pentazocine, Amiodarone, Carvedilol, Digoxin, Diltiazem, Nicardipine, Quinidine, Talinolol, Verapamil, Cyclosporine, Tacrolimus, Ivermectin, Milbemycin, Selamectin, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and any combination thereof.

[0050] In some embodiments of any one of the preceding embodiments, the additional characteristics of the sample or the subject comprise clinical data of the subject. In some embodiments, the clinical data of the subject is selected from the group consisting of: a stage of the lymphoma, length of time since diagnosis of the lymphoma, previous treatment regimens administered to the subject, treatment outcomes of the previous treatment regimens administered to the subject, and any combination thereof.

[0051] In some embodiments of any one of the preceding embodiments, the method further comprises: generating a physical or an electronic report about the predicted treatment outcome, a selected treatment regimen, additional characteristics of a sample from the subject or the subject, or a combination thereof. In some embodiments, the physical or the electronic report is delivered to (i) the subject or (ii) the caregiver or the medical provider for the subject.

[0052] In some embodiments of any one of the preceding embodiments, a sample obtained from the subject is a blood sample or a tumor sample.

[0053] In some embodiments of any one of the preceding embodiments, a sample obtained from the subject comprises blood cells or tumor cells.

[0054] In some embodiments of any one of the preceding embodiments, the subject is a mammal, optionally a human or a canine.Attorney Ref: 42800-64265 / WO (001WO)

[0055] In some embodiments of any one of the preceding embodiments, the subject has lymphoma selected from the group consisting of: B-cell lymphoma, T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and any combination thereof.

[0056] In some embodiments of any one of the preceding embodiments, the subject has B- cell lymphoma selected from the group consisting of: small B-cell lymphoma, medium B-cell lymphoma, large B-cell lymphoma, diffuse large B-cell lymphoma, and any combination thereof.

[0057] In some embodiments of any one of the preceding embodiments, the subject has T- cell lymphoma selected from the group consisting of: a helper-like CD4+ T cell lymphoma, a cytotoxic-like CD8+ T cell lymphoma, a CD45- T cell-zone lymphoma, an atypical T-cell lymphoma, and any combination thereof, optionally wherein the atypical T-cell lymphoma is a double negative T-cell lymphoma, a double positive T-cell lymphoma, an aberrant T-cell lymphoma, or any combination thereof.

[0058] One aspect of the present disclosure provides a kit comprising: a) one or more probes or one or more pairs of primers, wherein the one or more probes or the one or more pairs of primers are configured to hybridize with one or more target polynucleotides in a sample, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof, and b) instructions for reacting the one or more probes or the one or more pairs of primers with the sample, thereby enriching or amplifying the one or more target polynucleotides in the sample.

[0059] In some embodiments, the one or more probes or the one or more pairs of primers are configured to hybridize with one or more target polynucleotides in a sample, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A,Attorney Ref: 42800-64265 / WO (001WO)CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0060] In some embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF1 1A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more probes or the one or more pairs of primers are completely complementary to wild-type sequences specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1 , TNFRSF11 A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more probes or the one or more pairs of primers are completely complementary to sequences with one or more mutations specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0061] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to 21 different genes, 20 different genes, 19 different genes, 18 different genes, 17 different genes, 16 different genes, 15 different genes, 14 different genes, 13 different genes, 12 different genes, 11 different genes, 10 different genes, 9 different genes, 8 different genes, 7 different genes, 6 different genes, 5 different genes, 4 different genes, 3 different genes, 2 different genes or a single gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0062] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to at least 20 different genes, at least 19 different genes, at least 18 different genes, at least 17 different genes, at least 16 different genes, at least 15 different genes, at least 14 different genes, at least 13 different genes, at least 12 different genes, atAttorney Ref: 42800-64265 / WO (001WO) least 11 different genes, at least 10 different genes, at least 9 different genes, at least 8 different genes, at least 7 different genes, at least 6 different genes, at least 5 different genes, at least 4 different genes, at least 3 different genes, or at least 2 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0063] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to the first 20 genes, the first 19 genes, the first 18 genes, the first 17 genes, the first 16 genes, the first 15 genes, the first 14 genes, the first 13 genes, the first 12 genes, the first 1 1 genes, the first 10 genes, the first 9 genes, the first 8 genes, the first 7 genes, the first 6 genes, the first 5 genes, the first 4 genes, the first 3 genes, or the first 2 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0064] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, and TP53, or mammalian orthologs thereof.

[0065] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof.

[0066] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof.

[0067] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 and FBXW7, or mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (001WO)

[0068] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 and KMT2D, or mammalian orthologs thereof.

[0069] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD and CREBBP, or mammalian orthologs thereof.

[0070] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to CREBBP or a mammalian ortholog thereof.

[0071] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 or a mammalian ortholog thereof.

[0072] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to FBXW7 or a mammalian ortholog thereof.

[0073] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to CCND1 or a mammalian ortholog thereof.

[0074] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to KMT2C and a mammalian ortholog thereof.

[0075] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to NOTCH2 or a mammalian ortholog thereof.

[0076] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD or a mammalian ortholog thereof.Attorney Ref: 42800-64265 / WO (001WO)

[0077] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes selected from the group consisting of: SETD2, TP53, and TRAF3 or mammalian orthologs thereof.

[0078] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes selected from a-d, wherein a-d are: a) KMT2C and NOTCH2, or mammalian orthologs thereof, b) KMT2D and KMT2C, or mammalian orthologs thereof, c) KMT2C and BCL1 IB, or mammalian orthologs thereof, and d) KMT2D and NOTCH2, or mammalian orthologs thereof.

[0079] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes are selected from a-e, wherein a-e are: a) TRAF3 and SETD2 or mammalian orthologs thereof, b) TRAF3 and POTI, or mammalian orthologs thereof, c) TRAF3 and TBL1XR1, or mammalian orthologs thereof, d) TP53 and SETD2, or mammalian orthologs thereof, and e) POTI and FBXW7, or mammalian orthologs thereof.

[0080] In some embodiments of any one of the preceding embodiments, the one or more probes or the one or more pairs of primers comprise nucleic acid. In some embodiments, the nucleic acid is selected from the group consisting of: ribonucleic acid (RNA), deoxyribonucleic acid (DNA), 1,5-Anhydrohexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), fluoroarabino nucleic acid (FANA), and any combination thereof.

[0081] In some embodiments of any one of the preceding embodiments, the one or more probes are on one or more panels.

[0082] In some embodiments of any one of the preceding embodiments, the one or more probes are conjugated to a biotin molecule.

[0083] In some embodiments of any one of the preceding embodiments, the kit further comprises: a) a polymerase chain reaction (PCR) buffer, b) deoxynucleotide triphosphates (dNTPs), c) a polymerase, d) beads, e) universal primers, f) reaction buffer, g) a purificationAttorney Ref: 42800-64265 / WO (001WO) column, h), reagents for sequencing reaction, i) a fragmentation enzyme, and / or j) an end repair enzyme.

[0084] In some embodiments of any one of the preceding embodiments, each probe of the one or more probes comprises at least 120 nucleotides, at least 200 nucleotides at least 500 nucleotides, at least 1,000 nucleotides, at least 2,000 nucleotides, at least 3,000 nucleotides, at least 4,000 nucleotides or at least 5,000 nucleotides. In some embodiments of any one of the preceding embodiments, each probe of the one or more probes comprises 120-7,000 nucleotides. In some embodiments of any one of the preceding embodiments, each probe of the one or more probes comprises 200-5,000 nucleotides, 500-3,000 nucleotides, or 1,000- 2,000 nucleotides.

[0085] In some embodiments of any one of the preceding embodiments, each of the one or more probes comprises a nucleotide molecule having a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence of SEQ ID NOs: 22-578, or any combination thereof.

[0086] In some embodiments of any one of the preceding embodiments, each primer of the one or more pairs of primers comprises at least 15 nucleotides, 15-40 nucleotides, or 15-30 nucleotides.

[0087] In some embodiments of any one of the preceding embodiments, the one or more pairs of primers hybridize with a sequence of a polynucleotide with a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.

[0088] In some embodiments of any one of the preceding embodiments, each pair of the one or more pairs of primers are configured to configured to amplify a sequence of at least 50bp, at least lOObp, at least 500bp, at least lOOObp, at least 2000bp, at least 3000bp or at least 5000bp in the gene selected from KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1,Attorney Ref: 42800-64265 / WO (001WO)ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL,. PIK3CD, FBXW7, and mammalian orthologs thereof. In some embodiments, the amplified sequence comprises a sequence corresponding to one or more exons of gene selected from KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1 , SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, F0XL2, PIK3CD, FBXW7, and mammalian orthologs thereof.

[0089] In some embodiments of any one of the preceding embodiments, the one or more target polynucleotides comprise a sequence of a polynucleotide with a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof. In some embodiments, the one or more target polynucleotides comprise a polynucleotide of a sequence specific to a sequence selected from the group consisting of: SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.

[0090] In some embodiments of any one of the preceding embodiments, the one or more probes or one or more pairs of primers are conjugated to a dye. In some embodiments, the dye is a fluorescent dye. In some embodiments, the one or more probes or one or more pairs of primers are conjugated to a quencher.

[0091] In some embodiments of any one of the preceding embodiments, the kit further comprises a reagent for qPCR.Attorney Ref: 42800-64265 / WO (001WO)

[0092] One aspect of the present disclosure provides a method for obtaining sequence information for treatment of a subject with lymphoma, comprising: a) obtaining a sample from the subject, b) reacting the sample with one or more probes, wherein the one or more probes are configured to hybridize with one or more target polynucleotides, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof, c) enriching the one or more target polynucleotides in the sample, and d) obtaining sequence information of the one or more target polynucleotides.

[0093] In some embodiments, wherein the one or more probes are in the kit of any of one of the preceding embodiments.

[0094] One aspect of the present disclosure provides a method for obtaining sequence information for treatment of a subject with lymphoma, comprising: a) obtaining a sample from the subject, b) reacting the sample with one or more primers, wherein the one or more primers are configured to hybridize with one or more target polynucleotides, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof, c) amplifying the one or more target polynucleotides in the sample, and d) obtaining sequence information of the one or more target polynucleotides.

[0095] In some embodiments, the one or more primers are in the kit of any of one of the preceding embodiments.

[0096] One aspect of the present disclosure provides a diagnostic product of predicting a treatment outcome of a subject with lymphoma, wherein the diagnostic product is stored on a non-transitory computer readable medium and is manufactured by a process comprising: obtaining information related to a set of candidate genes, retrieving a set of training samples, each training sample comprises mutation information in the candidate genes of training subjects and treatment outcomes of the training subjects, applying a K-means clustering algorithm to the training samples to divide the training samples into a plurality of clustersAttorney Ref: 42800-64265 / WO (001WO) based on the mutation information in the candidate genes and the treatment outcomes, and determining a quality of the clusters based on treatment outcomes of separate clusters.

[0097] In some embodiments, the process further comprises: repeating the preceding steps of obtaining, retrieving, applying and determining for a set of different candidate genes, and selecting a final set of genes based on the quality of the clusters corresponding to the multiple sets of candidate genes.

[0098] In some embodiments, the step of determining the quality of the clusters is performed based on separation of different outcomes by the clusters, optionally wherein the separation of different outcomes is based on survival. In some embodiments, the step of determining the quality of the clusters is performed based on a p- value between two or more separate clusters in predicting the treatment outcomes. In some embodiments, a set of candidate genes that provides a p-value between two or more clusters larger than a threshold is not selected as the final set of genes.

[0099] In some embodiments, the step of determining the quality of the clusters is performed based on a hazard ratio between two or more clusters.

[0100] In some embodiments of any one of the preceding embodiments, the candidate genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof.

[0101] One aspect of the present disclosure provides a method of predicting the treatment outcome of a test subject comprises: extracting the features related to one or more mutations of the test subject in a set of genes that are selected for a particular treatment regimen, classifying, using the diagnostic product of any one of the preceding embodiments, the subject into one of the plurality of clusters, and predicting, using the classified cluster, the treatment outcome of the particular treatment regimen.

[0102] One aspect of the present disclosure provides a diagnostic product for selecting a treatment regimen for a subject with lymphoma, wherein the diagnostic product is stored on a non-transitory computer readable medium and is manufactured by a process comprising:Attorney Ref: 42800-64265 / WO (OOIWO) obtaining sequence information of one or more genes in a plurality of subjects, wherein the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, F0XL2, PIK3CD, FBXW7, and mammalian orthologs thereof, obtaining a training dataset including a plurality of training examples, wherein each training example comprises the sequence information of an individual subject and a treatment outcome of the individual subject in response to the treatment regimen, numerically encoding the training examples in the training dataset, comprising numerically encoding the sequence information of the individual subject or mutation information identified from the sequence information, and numerically encoding the treatment outcome of the individual subject in response to the treatment regimen, for a diagnostic model comprising a machine learning model that has a plurality of layers, each layer having a plurality of parameters, the layers comprising an input layer for receiving the numerically encoded sequence information or mutation information and an output layer indicating a treatment outcome in response to the treatment regimen, for one or more iterations of the training process: (a) for a set of training examples for the current iteration, applying parameters of the machine learning model to generate estimated likelihoods for the set of training examples, (b) computing a loss function indicating a difference between the estimated likelihoods and the numerically encoded treatment outcome for the set of training examples for the current iteration, (c) repeatedly backpropagating one or more error terms obtained from the loss function, to update the parameters of the layers of the diagnostic model, and (d) stopping the backpropagation after the loss function satisfies a criterion, and storing the updated set of parameters for the layers of the diagnostic model on the computer readable storage medium.

[0103] One aspect of the present disclosure provides a method of treating a test subject with lymphoma, comprising: obtaining sequence information of one or more genes in the test subject, wherein the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof, applying the sequence information or mutation information obtained from theAttorney Ref: 42800-64265 / WO (001WO) sequence information to the diagnostic product of the preceding embodiment, thereby predicting a treatment outcome of the test subject, and providing information related to the prediction to (i) the test subject or (ii) a care giver or a medical provider for the test subject for use in treatment of the test subject.

[0104] In some embodiments, the method further comprises: generating a physical or electronic report related to the prediction. In some embodiments, the method further comprises: selecting a treatment regimen based on the prediction.

[0105] In some embodiments of any one of the preceding embodiments, the method further comprises: treating the test subject by the selected treatment regimen.4. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0106] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0107] FIGURE 1 illustrates an oncoplot depicting somatic mutations of the top 35 genes in the analysis of a cohort of 238 dogs, segmented by the major immunophenotypic subtypes of canine lymphoma. Demographic characteristics of the cohort are shown in a secondary heatmap.

[0108] FIGURE 2 illustrates a circle plot showing co-mutations with greater than 20 cooccurrences among the most frequently somatically mutated genes in the cohort. Outer rings represent the total number of pair-wise co-mutations detected.

[0109] FIGURE 3A illustrates the overall survival (OS) for CHOP / L-CHOP therapy in TRAF3 for somatic loss-of-function (LOF) mutations in B-cell lymphomas (BCLs).

[0110] FIGURE 3B illustrates the progression free survival (PFS) for CHOP / L-CHOP therapy in TRAF3 for somatic LOF mutations in BCLs.

[0111] FIGURE 3C illustrates the duration of response (DOR) for CHOP / L-CHOP therapy in TRAF3 for somatic LOF mutations in BCLs.

[0112] FIGURE 3D illustrates the time to response (TTR) for CHOP / L-CHOP therapy in TRAF3 for somatic LOF mutations in BCLs.Attorney Ref: 42800-64265 / WO (001WO)

[0113] FIGURE 3E illustrates the OS for CHOP / L-CHOP therapy in TRAF3 for germline LOF mutations in BCLs.

[0114] FIGURE 3F illustrates the PFS for CHOP / L-CHOP therapy in TRAF3 for germline LOF mutations in BCLs.

[0115] FIGURE 3G illustrates the DOR for CHOP / L-CHOP therapy in TRAF3 for germline LOF mutations in BCLs.

[0116] FIGURE 3H illustrates the TTR for CHOP / L-CHOP therapy in TRAF3 for germline LOF mutations in BCLs.

[0117] FIGURE 4A illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following partial response (PR) in T-cell lymphomas (TCLs) to all CHOP-like regimens according to somatic mutations status in PIK3CD.

[0118] FIGURE 4B illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following complete response (CR) in TCLs to CHOP / L-CHOP regimens according to somatic mutations status in NOTCH2.

[0119] FIGURE 4C illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following CR in TCLs to CHOP / L-CHOP regimens according to somatic mutations status in KMT2C.

[0120] FIGURE 4D illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following PR in TCLs to Lomustine-containing regimens according to somatic mutations status in CREBBP.

[0121] FIGURE 4E illustrates a Kaplan Meier curve for a putative biomarker predictive of OS following CR in BCLs to CHOP / L-CHOP regimens according to somatic mutations status in FBXW7.

[0122] FIGURE 4F illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following CR in BCLs to CHOP / L-CHOP regimens according to somatic mutations status in TRAF3.Attorney Ref: 42800-64265 / WO (001WO)

[0123] FIGURE 4G illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following CR in BCLs to CHOP / L-CHOP regimens according to somatic mutations status in KMT2D.

[0124] FIGURE 4H illustrates a Kaplan Meier curve for a putative biomarker predictive of PFS following PR in BCLs to Tanovea-containing regimens according to somatic mutations status in CCND1.

[0125] FIGURE 5A illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of Doxorubicin treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include MTOR, KLF4, and VEGFA, in accordance with some embodiments.

[0126] FIGURE 5B illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of Doxorubicin treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include MTOR, KLF4, and ITK, in accordance with some embodiments.

[0127] FIGURE 6A illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of Tanovea treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include CCND1, KMT2D, TP53, and ARID1A, in accordance with some embodiments.

[0128] FIGURE 6B illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of Tanovea treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include CCND1, TNFRSF11 A, SLC19A1, and TP53, in accordance with some embodiments.

[0129] FIGURE 6C illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of Tanovea treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include CCND1 and TP53, in accordance with some embodiments.

[0130] FIGURE 7A illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of CCNU treatment of two clusters ofAttorney Ref: 42800-64265 / WO (001WO) training sample subjects with lymphoma using a selected set of genes that include TP53, SETD2, and SLC7A5, in accordance with some embodiments.

[0131] FIGURE 7B illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of CCNU treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include GNA13, TP53, and ENSCAFG00000001448, in accordance with some embodiments.

[0132] FIGURE 7C illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of CCNU treatment of two clusters of training sample subjects with lymphoma using a selected set of genes that include EP3000, ABCC5, and FOXL2, in accordance with some embodiments.

[0133] FIGURE 8A illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of CHOP treatment of 9 different clusters of training sample subjects with lymphoma using a selected set of genes that include PIK3CD, CREBBP, FBXW7, and TRAF3, in accordance with some embodiments.

[0134] FIGURE 8B illustrates the result of a K-means clustering model in the form of Kaplan Meier curves for predicting treatment outcomes of CHOP treatment by further grouping the 9 clusters into two groups, in accordance with some embodiments.

[0135] FIGURE 9 illustrates the structure of an example neural network, in accordance with some embodiments.5. DETAILED DESCRIPTION OF THE INVENTION5.1. Definitions

[0136] The term “therapeutic outcome” as used herein refers to a response of a subject with a disease (e.g., cancer) in response to a treatment regimen. The treatment outcome can be shortterm and long-term response.

[0137] The term “positive response” as used herein refers to a desired or preferred therapeutic outcome of a subject with a disease (e.g., cancer) in response to a treatment regimen. A positive response can be associated with recovery, slowed progression of cancer, improvement of signs (e.g., tumor cell lysis, decrease in tumor size, no or reduced metastasis), improvement of symptoms (e.g., fever, fatigue, pain, weight loss) of a disease,Attorney Ref: 42800-64265 / WO (OOIWO) and / or no new signs associated with the disease appearing. For example, a positive response to a treatment regimen can comprise one or more treatment outcomes selected from the group consisting of: a partial response, a complete response, an increase in overall survival (OS), an increase in progression free survival (PFS), an increase in duration of response (DOR), a decrease in time to response (TTR), an increase in disease free survival (DFS), an increase in time to progression (TTP), an increase in event-free survival (EFS), an increase in time to next treatment (TTNT), and any combination thereof.

[0138] The term “negative response” as used herein refers to an undesired therapeutic outcome of a subject with a disease in response to a treatment regimen. A negative response can be associated with a worsening of a symptom of the disease in the subject (e.g., increase in tumor size, fever, fatigue, pain, weight loss ), and / or progression of the disease in the patient (e.g., metastasis). A negative response to a treatment regimen can comprise one or more treatment outcomes selected from the group consisting of: progressive disease (PD), a decrease in OS, a decrease in PFS, a decrease in DOR, an increase in TTR, a decrease in DFS, a decrease in TTP, a decrease in EFS, a decrease in TTNT, and any combination thereof.5.2. Method of treating a subject with a cancer

[0139] The present disclosure provides a method of treating a subject with a cancer. In some embodiments, the method comprising: a) obtaining sequence information of one or more genes in the subject, wherein the one or more genes comprise: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, MYC, BRCA1, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and / or mammalian orthologs thereof; b) based on the sequence information, predicting a treatment outcome of the subject; and c) providing information related to the prediction to (i) the subject or (ii) a care giver or a medical provider for the subject for use in treatment of the subject. In some embodiments, one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF1 1A, ABCC4, ATM, MYC, BRCA1, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof. In some embodiments, the one or more genes are selectedAttorney Ref: 42800-64265 / WO (001WO) from KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, or mammalian orthologs thereof.

[0140] In some embodiments, the sequence information comprises the sequences of the one or more genes in the subject. In some embodiments, the sequences of the one or more genes in the subject are ribonucleic acid (RNA) sequences. In some embodiments, the RNA sequences are one or more RNA sequence selected from the group consisting of: messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), piwi-interacting RNA (piRNA), microRNA (miRNA), small interfering RNA (siRNA), long noncoding RNA (IncRNA), and any combination thereof. In some embodiments, the sequences of the one or more genes in the subject are deoxyribonucleic acid (DNA) sequences. In some embodiments, the DNA sequences are genomic DNA sequences. In some embodiments, the genomic DNA sequences are nuclear DNA sequences. In some embodiments, the genomic DNA sequences are mitochondrial DNA sequences.

[0141] In some embodiments, the sequences of the one or more genes in the subject comprises one or more mutations. In some embodiments, the sequence information detects a presence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, the sequence information detects an absence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, the sequence information detects (i) a presence of the one or more mutations and (ii) an absence of the one or more mutations in the sequences of the one or more genes in the subject.

[0142] In some embodiments, the sequence information obtained is provided in a computer file. In some embodiments, the sequence information obtained is provided in one or more computer files selected from the group consisting of: genome browsers, BED files, GFF files, GTF files, VCF files, FASTA files, FASTQ files, BAM files, SAM files, and any combination thereof.

[0143] In some embodiments, the treatment outcome of the subject is a positive response to a treatment regimen. In some embodiments, a positive response to a treatment regimen comprises one or more treatment outcomes selected from the group consisting of: a partialAttorney Ref: 42800-64265 / WO (OOIWO) response, a complete response, an increase in overall survival (OS), an increase in progression free survival (PFS), an increase in duration of response (DOR), a decrease in time to response (TTR), an increase in disease free survival (DFS), an increase in time to progression (TTP), an increase in event-free survival (EFS), an increase in time to next treatment (TTNT), and any combination thereof.

[0144] In some embodiments, a positive response to a treatment regimen is a partial response to the treatment regimen. A partial response to a treatment regimen can refer to a decrease in a size of a tumor or a decrease in the amount of cancer in the subject following administration of the treatment regimen. In some embodiments, a positive response to a treatment regimen is a complete response to the treatment regimen. A complete response to a treatment regimen can refer to a disappearance of all signs of cancer in the subject following administration of the treatment regimen. In some embodiments, a positive response to a treatment regimen is an increase in OS. Overall survival can refer the length of time from the start of the treatment regimen that the subject with the cancer is still alive. An increase in OS from the treatment regimen can be an increase in the length of time from the start of the treatment regimen (e.g., timepoint #1) that the subject with the cancer is still alive compared to the length of time from timepoint #1 that another subject with the cancer that did not receive the treatment regimen is still alive. In some embodiments, a positive response to a treatment regimen is an increase in PFS. Progression free survival can refer to the length of time during and after administration of the treatment regimen that the subject lives with the cancer, but the cancer does not get worse. An increase in PFS from the treatment regimen can be an increase in the length of time during or after administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before the cancer progressing compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the cancer progresses. In some embodiments, a positive response to a treatment regimen is an increase in DOR. Duration of response can refer to the length of time the subject responds to the treatment regimen without tumor growth or metastasis. An increase in DOR from the treatment regimen can be an increase in the length of time the subject with cancer responds to the treatment regimen without tumor growth or metastasis following administration of the treatment regimen (e.g., timepoint #1) compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen without tumor growth or metastasis. In some embodiments, a positive response to a treatment regimen is a decrease in TTR. Time to response can refer to theAttorney Ref: 42800-64265 / WO (OOIWO) length of time from the initial administration of the treatment regimen to a first occurrence of response to the treatment regimen in the subject. A decrease in TTR from the treatment regimen can be a decrease in the length of time following initial administration of the treatment regimen (e.g., timepoint #1) that the subject with the cancer exhibits a first occurrence of response to the treatment regimen compared to the length of time from timepoint #1 that another subject with the cancer that received a different treatment regimen exhibits a first occurrence of response of the different treatment regimen. In some embodiments, a positive response to a treatment regimen is an increase in DFS. Disease free survival can refer to the length of time during and after administration of the treatment regimen where there is not evidence of disease recurrence in the subject. An increase in DFS from the treatment regimen can be an increase in the length of time during or after administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before a first incidence of disease recurrence compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the first incidence of disease recurrence. In some embodiments, a positive response to a treatment regimen is an increase in TTP. Time to progression can refer to the length of time following administration of the treatment regimen until first evidence of cancer progression. An increase in TTP from the treatment regimen can be an increase in the length of time following administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before a first incident of progression compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the first incident of progression. In some embodiments, a positive response to a treatment regimen is an increase in EFS. Event- free survival can refer to the length of time following initial administration of the treatment regimen to disease progression, discontinuation of the treatment regimen, or death. An increase in EFS from the treatment regimen can be an increase in the length of time following initial administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before disease progression, discontinuation of the treatment regimen, or death compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before disease progression, discontinuation of the treatment regimen, or death. In some embodiments, a positive response to a treatment regimen is an increase in TTNT. Time to next treatment can refer to the length of time from initiating the treatment regimen to a second line of therapy. An increase in TTNT from the treatment regimen can be an increase in the length of time following initiation of the treatment regimen (e.g., timepointAttorney Ref: 42800-64265 / WO (OOIWO)#1) that the subject lives with the cancer before a second line of therapy is started compared to the length of time from timepoint #1 that another subject lives with the cancer that received a different treatment regimen before a second line of therapy is started.

[0145] In some embodiments, the treatment outcome of the subject is a negative response to a treatment regimen. In some embodiments, a negative response to a treatment regimen comprises one or more treatment outcomes selected from the group consisting of: progressive disease (PD), a decrease in OS, a decrease in PFS, a decrease in DOR, an increase in TTR, a decrease in DFS, a decrease in TTP, a decrease in EFS, a decrease in TTNT, and any combination thereof.

[0146] In some embodiments, a negative response to a treatment regimen is progressive disease. Progressive disease can refer to when the amount of cancer in the subject increases following administration of the treatment regimen. In some embodiments, a negative response to a treatment regimen is a decrease in OS. A decrease in OS from the treatment regimen can be a decrease in the length of time from the start of the treatment regimen (e.g., timepoint #1) that the subject with the cancer is still alive compared to the length of time from timepoint #1 that another subject with the cancer that did not receive the treatment regimen is still alive. In some embodiments, a negative response to a treatment regimen is a decrease in PFS. A decrease in PFS from the treatment regimen can be a decrease in the length of time during or after administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before the cancer progressing compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the cancer progresses. In some embodiments, a negative response to a treatment regimen is a decrease in DOR. A decrease in DOR from the treatment regimen can be a decrease in the length of time the subject with cancer responds to the treatment regimen without tumor growth or metastasis following administration of the treatment regimen (e.g., timepoint #1) compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen without tumor growth or metastasis. In some embodiments, a negative response to a treatment regimen is an increase in TTR. An increase in TTR from the treatment regimen can be an increase in the length of time following initial administration of the treatment regimen (e.g., timepoint #1) that the subject with the cancer exhibits a first occurrence of response to the treatment regimen compared to the length of time from timepoint #1 that another subject with the cancer thatAttorney Ref: 42800-64265 / WO (OOIWO) received a different treatment regimen exhibits a first occurrence of response of the different treatment regimen. In some embodiments, a negative response to a treatment regimen is a decrease in DFS. A decrease in DFS from the treatment regimen can be a decrease in the length of time during or after administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before a first incidence of disease recurrence compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the first incidence of disease recurrence. In some embodiments, a negative response to a treatment regimen is a decrease in TTP. A decrease in TTP from the treatment regimen can be a decrease in the length of time following administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before a first incident of progression compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before the first incident of progression. In some embodiments, a negative response to a treatment regimen is a decrease in EFS. A decrease in EFS from the treatment regimen can be a decrease in the length of time following initial administration of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before disease progression, discontinuation of the treatment regimen, or death compared to the length of time from timepoint #1 that another subject lives with the cancer that did not receive the treatment regimen before disease progression, discontinuation of the treatment regimen, or death. In some embodiments, a negative response to a treatment regimen is a decrease in TTNT. A decrease in TTNT from the treatment regimen can be a decrease in the length of time following initiation of the treatment regimen (e.g., timepoint #1) that the subject lives with the cancer before a second line of therapy is started compared to the length of time from timepoint #1 that another subject lives with the cancer that received a different treatment regimen before a second line of therapy is started.

[0147] Alternatively, in some embodiments, a response to a treatment regimen is stable disease to the treatment regimen. Stable disease can refer to when the amount of cancer in the subject remains the same following administration of the treatment regimen.

[0148] In some embodiments, the predicting the treatment outcome of the subject is based on a presence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, the predicting the treatment outcome of the subject is based on an absence of the one or more mutations in the sequences of the one or more genes in theAttorney Ref: 42800-64265 / WO (OOIWO) subject. In some embodiments, the predicting the treatment outcome of the subject is based on (i) a presence of the one or more mutations and (ii) an absence of the one or more mutations in the sequences of the one or more genes in the subject.5.2.1. Subjects

[0149] In some embodiments, the method disclosed herein is used on a mammalian subject. In some embodiments, the mammal is selected from the group consisting of: human, feline, canine, cattle, pig, sheep, horse, goat, donkey, rabbit, ferret, llama, buffalo, any and combination thereof. In some embodiments, the subject is a human. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. In some embodiments, the subject is a rabbit. In some embodiments, the subject is a bird. In some embodiments, the bird is selected from the group consisting of: duck, parrot, parakeet, lovebird, finch, macaw, goose, and any combination thereof. In some embodiments, the biological sex of the subject is male. In some embodiments, the biological sex of the subject is female.

[0150] In some embodiments, the subject has cancer. Non-limiting examples of cancer includes acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, Kaposi sarcoma, AIDS-related lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, Ewing sarcoma, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, Non-Hodgkin lymphoma, metdulloblastoma, CNS embryonal tumors, germ cell tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ, diffuse intrinsic pontine glioma, embryonal tumors, medulloblastoma, endometrial cancer, uterine cancer, ependymoma, brain cancer, esophageal cancer, head and neck cancer, esthesioneuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, gallbladder cancer, stomach cancer, gastrointestinal neuroendocrine tumors, gastrointestinal stromal tumors, soft tissue sarcoma, ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, heart tumors, liver cancer, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, eye cancer, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi Sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer,Attorney Ref: 42800-64265 / WO (OOIWO) leukemia, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, pleuropulmonary blastoma, pulmonary inflammatory myofibroblastic tumor, tracheobronchial tumor, lymphoma, male breast cancer, melanoma, Merkel cell carcinoma, skin cancer, mesothelioma, metastatic cancer, metastatic squamous neck cancer with occult primary, midline track carcinoma with NUT gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, chronic myelogenous leukemia, acute myeloid leukemia, chronic myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, neuroendocrine tumors, gastrointestinal cancer, oral cancer, oropharyngeal cancer, osteosarcoma, undifferentiated pleomorphic sarcoma of bone treatment, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, primary perioneal cancer, prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, childhood vascular tumors, uterine sarcoma, Sezary syndrome, skin cancer, small intestine cancer, squamous cell carcinoma of the skin, testicular cancer, throat cancer, thymoma cancer, thymic cancer, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, urethral cancer, endometrial uterine cancer, splenic cancer, vaginal cancer, vascular tumors, vulvar cancer, Wilms tumor, fibrosarcoma, hemangiosarcoma, oral tumors, abdominal tumors, intestinal adenocarcinomas, mastocytoma, mammary gland carcinoma, transitional cell carcinoma, histiocytic sarcoma, anal sac cancer, mast cell tumors, oral melanoma, or any combination thereof.

[0151] In some embodiments, the subject has lymphoma. In some embodiments, the lymphoma is selected from the group consisting of: B-cell lymphoma (BCL), T-cell lymphoma (TCL), Burkitt’s lymphoma, Hodgkin lymphoma, Non-Hodgkin lymphoma, AIDS-related lymphoma, Mycosis Fungoides, primary CNS lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Posttransplant lymphoproliferative disorder, marginal zone lymphoma, Waldenstrom’s macroglobulinemia, anaplastic large cell lymphoma, Sezary syndrome, peripheral T cell lymphoma not otherwise specified, angioimmunoblastic lymphoma, hepatosplenic T-cell lymphoma, extranodal NK / T-cell lymphoma, cutaneous T-cell lymphoma, classic Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and any combination thereof. In some embodiments, the lymphoma is selected from the group consisting: BCL,Attorney Ref: 42800-64265 / WO (OOIWO)TCL, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal BCL small lymphocytic lymphoma, lymphoplasmacytic lymphoma, gastrointestinal lymphoma, mediastinal lymphoma, renal lymphoma, and any combination thereof.

[0152] In some embodiments, the lymphoma is BCL. In some embodiments, the BCL is diffuse large BCL, follicular lymphoma, primary mediastinal BCL, mantle cell lymphoma, Post-transplant lymphoproliferative disorder, marginal zone lymphoma, Waldenstrom’s macroglobulinemia, Burkitt’s lymphoma, small BCL, medium BCL, large BCL, or any combination thereof. In some embodiments, the BCL is selected from the group consisting: small B-cell lymphoma, medium B-cell lymphoma, large B-cell lymphoma, diffuse large B- cell lymphoma, and any combination thereof. In some embodiments, the BCL is diffuse large BCL. In some embodiments, the BCL is small BCL. In some embodiments, the BCL is medium BCL. In some embodiments, the BCL is large BCL.

[0153] In some embodiments, the lymphoma is TCL. In some embodiments, the TCL is anaplastic large cell lymphoma, peripheral T cell lymphoma not otherwise specific, angioimmunoblastic lymphoma, hepatosplenic T-cell lymphoma, extranodal NK / T-cell lymphoma, cutaneous TCL, helper-like CD4+ TCL, cytotoxic-like CD8+ TCL, CD45-T cellzone lymphoma, atypical TCL, or any combination thereof. In some embodiments, the TCL is selected from the group consisting of: a helper- like CD4+ T cell lymphoma, a cytotoxic- like CD8+ T cell lymphoma, a CD45- T cell-zone lymphoma, an atypical T-cell lymphoma, and any combination thereof. In some embodiments, the atypical T-cell lymphoma is a double negative T-cell lymphoma (e.g., CD3+ / CD4- / CD8-), a double positive T-cell lymphoma (e.g., CD3+ / CD4+ / CD8-I-), or an aberrant (CD3-) T cell lymphoma, or any combination thereof. Tn some embodiments, the aberrant T cell lymphoma is CD3- T cell lymphoma. In some embodiments, the TCL is a helper-like CD4+ T cell lymphoma. In some embodiments, the TCL is a cytotoxic-like CD8+ T cell lymphoma. In some embodiments, the TCL is a CD45- T cell-zone lymphoma. In some embodiments, the TCL is an atypical T-cell lymphoma.

[0154] In some embodiments, the lymphoma is Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is nodular lymphocyte-predominant Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is classic Hodgkin lymphoma. In some embodiments, the classic Hodgkin lymphoma is modular sclerosing Hodgkin lymphoma, mixed cellularityAttorney Ref: 42800-64265 / WO (OOIWO)Hodgkin lymphoma, lymphocyte depleted Hodgkin lymphoma, and lymphocyte rich Hodgkin lymphoma, or any combination thereof.

[0155] In some embodiments, the lymphoma is Non- Hodgkin lymphoma. In some embodiments, the Non-Hodgkin lymphoma is diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, peripheral T cell lymphoma, follicular lymphoma, cutaneous T cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, small cell lymphocytic lymphoma, chronic lymphocytic lymphoma, precursor T-lymphoblastic lymphoma, adult T- cell lymphoma, primary mediastinal B cell lymphoma, primary CNS lymphoma, mucosa- associated lymphoid tissue lymphoma, modal marginal zone B cell lymphoma splenic marginal zone B cell lymphoma, cutaneous T cell lymphoma, mycosis fungoides, Sezary syndrome, primary cutaneous anaplastic large-cell lymphoma peripheral T cell lymphoma, angioimmunoblastic T cell lymphoma, anaplastic large cell lymphoma (ALCL), primary cutaneous ALCL, systemic ALCL, enteropathy-type T cell lymphoma, hepatosplenic gamma / delta T cell lymphoma, or any combination thereof.

[0156] In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is chronic lymphocytic leukemia, precursor T-lymphoblastic leukemia, adult T-cell leukemia, Hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, large granular lymphocytic leukemia, T-cell prolymphocytic leukemia, myeloproliferative neoplasms, systemic mastocytosis, chronic eosinophilic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, essential thrombocythemia, polycythemia vera, primary myelofibrosis, chronic idiopathic myelofibrosis, or any combination thereof. In some embodiments, the leukemia is acute myeloid leukemia.

[0157] In some embodiments, the cancer is a myeloma. In some embodiments, the myeloma is multiple myeloma. In some embodiments, the multiple myeloma is hyperdiploid, hypodiploid, light chain myeloma, non-secretory myeloma, solitary plasmacytoma, multiple solitary plasmacytoma, extramedullary plasmacytoma, extramedullary myeloma, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, immunoglobulin D (IgD) myeloma, immunoglobulin E (IgE) myeloma, active multiple myeloma,Attorney Ref: 42800-64265 / WO (OOIWO) immunoglobulin A (IgA) myeloma, immunoglobulin G (IgG) myeloma, immunoglobulin M (IgM) myeloma, or any combination thereof.

[0158] In some embodiments, the cancer is a carcinoma. In some embodiments, the carcinoma is squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, basal cell carcinoma, or any combination thereof. In some embodiments, the cancer is a sarcoma. In some embodiments, the sarcoma is a soft tissue sarcoma or a bone sarcoma. In some embodiments, the sarcoma is bone sarcoma, a soft tissue sarcoma, angiosarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, Ewing’s sarcoma, fibrosarcoma, gastrointestinal stromal tumors, Kaposi sarcoma, chondrosarcoma, rhabdomyosarcoma, myeloid sarcoma, osteosarcoma, pleomorphic sarcoma, spindle cell sarcoma, synovial sarcom, leiomyosarcoma, or any combination thereof. In some embodiments, the cancer is a central nervous system cancer. In some embodiments, the CNS cancer is gliomas, astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, meningiomas, medulloblastomas, gangliogliomas, Schwannomas, craniopharyngiomas, medulloblastomas, oligoastrocytomas, or any combination thereof. In some embodiments, the cancer is a solid tumor cancer. Non-limiting examples of solid tumor cancers include breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, colon cancer, skin cancer, brain cancer, ovarian cancer, testicular cancer, uterine cancer, mast cell tumors, or any combination thereof. In some embodiments, the cancer is a mast cell tumor.

[0159] In some embodiments, the subject has been diagnosed with a cancer. In some embodiments, the subject has been diagnosed with a lymphoma. In some embodiments, the subject has been diagnosed with a leukemia. In some embodiments, the subject has been diagnosed with a myeloma. In some embodiments, the subject has been diagnosed with a mast cell tumor.5.2.2. Sample Types

[0160] In some embodiments, the method comprises analyzing a biological sample. In some embodiments, the biological sample comprises a biological fluid sample. In some embodiments, the biological fluid sample comprises whole blood, plasma, serum, saliva, lymphatic fluid, cerebrospinal fluid, urine, interstitial fluid, or any combination thereof. In some embodiments, the biological fluid sample comprises biological fluid cells. In some embodiments, the biological fluid sample comprises whole blood. In some embodiments, the biological fluid sample comprises blood cells. In some embodiments, the biological sampleAttorney Ref: 42800-64265 / WO (001WO) comprises a tissue sample. In some embodiments, the tissue sample comprises a healthy tissue sample. In some embodiments, a healthy tissue sample may not comprise any neoplastic tissue. In some embodiments, the tissue sample comprises tissue cells. In some embodiments, the tissue sample comprises a diseased tissue sample. In some embodiments, the diseased tissue sample comprises a neoplastic tissue sample. In some embodiments, the neoplastic tissue sample comprises a tumor sample. In some embodiments, the tissue sample comprises tumor cells. In some embodiments, the tumor sample comprises a lymphoma tumor sample.

[0161] In some embodiments, the biological sample comprises a biological fluid sample or a tissue sample. In some embodiments, the biological sample comprises a whole blood sample or a tumor sample. In some embodiments, the biological sample comprises a biological fluid sample and a tissue sample. In some embodiments, the biological sample comprises a whole blood sample and a tumor sample.

[0162] In some embodiments, the sample comprises a purified nucleic acid sample. In some embodiments, the purified nucleic acid sample comprises DNA molecules. In some embodiments, the purified nucleic acid sample comprises RNA molecules. In some embodiments, the purified nucleic acid sample comprises DNA molecules and RNA molecules. In some embodiments, the purified nucleic acid sample is derived from the biological sample.5.2.3. Sequence information

[0163] In some embodiments, the method further comprises a preceding step of generating the sequence information by analyzing a sample of the subject.

[0164] The sequence information can comprise a nucleotide sequence of a target polynucleotide, presence or absence of a mutation in the target polynucleotide, abundance of a mutation in the target polynucleotide, a type of the mutation, combination of one or more mutations, abundance of the target polynucleotide of a particular sequence, or other sequence information.

[0165] In some embodiments, the sample of the subject is a biological sample. In some embodiments, the sample comprises one or more target polynucleotides and one or more nontarget polynucleotides. In some embodiments, the one or more target polynucleotidesAttorney Ref: 42800-64265AVO (001WO) comprise the one or more genes. In some embodiments, the one or more target polynucleotides comprise one or more sequences specific to the one or more genes. In some embodiments, the one or more non-target polynucleotides may not comprise the one or more sequences specific to the one or more genes. In some embodiments, the one or more nontarget polynucleotides may not comprise the one or more genes. In some embodiments, the generating the sequence information step precedes the obtaining the sequence information step. In some embodiments, the sample comprises one or more polynucleotides. In some embodiments, the one or more polynucleotides comprise DNA molecules. In some embodiments, the one or more polynucleotides comprise RNA molecules. In some embodiments, the one or more polynucleotides comprise RNA molecules and DNA molecules.

[0166] In some embodiments, the sequence information is generated at a physician’s office. In some embodiments, the sequence information is generated at an outside laboratory separate from the physician’s office.

[0167] In some embodiments, the step of generating the sequence information comprises contacting the sample with one or more probes. In some embodiments, the contacting the sample with the one or more probes induces hybridization of one or more target polynucleotides. In some embodiments, the contacting the sample with the one or more probes comprises incubating the one or more probes with the sample. In some embodiments, the one or more probes are incubated with the sample for between 0 minutes to 24 hours. In some embodiments, the one or more probes are incubated with the sample for at least or up to 0 minutes, at least or up to 15 minutes, at least or up to 30 minutes, at least or up to 45 minutes, at least or up to 60 minutes, at least or up to 75 minutes, at least or up to 90 minutes, at least or up to 105 minutes, at least or up to 120 minutes, at least or up to 3 hours, at least or up to 4 hours, at least or up to 5 hours, at least or up to 6 hours, at least or up to 7 hours, at least or up to 8 hours, at least or up to 9 hours, at least or up to 10 hours, at least or up to 11 hours, at least or up to 12 hours, at least or up to 13 hours, at least or up to 14 hours, at least or up to 15 hours, at least or up to 16 hours, at least or up to 17 hours, at least or up to 18 hours, at least or up to 19 hours, at least or up to 20 hours, at least or up to 21 hours, at least or up to 22 hours, at least or up to 23 hours, or at least or up to 24 hours. In some embodiments, the one or more probes are incubated with the sample for 0 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 hours, 90 minutes, 105 minutes, 120Attorney Ref: 42800-64265 / WO (OOIWO) minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.

[0168] In some embodiments, the one or more probes are incubated with the sample at one or more temperatures. In some embodiments, one or more temperatures comprise at least or up to one temperature, at least or up to two temperatures, at least or up to three temperatures, at least or up to four temperatures, at least or up to five temperatures, at least or up to six temperatures, at least or up to seven temperatures, at least or up to eight temperatures, at least or up to nine temperatures, or at least or up to ten temperatures. In some embodiments, the one or more temperatures comprise one temperature, two temperatures, three temperatures, four temperatures, five temperatures, six temperatures, seven temperatures, eight temperatures, nine temperatures, or ten temperatures. In some embodiments, the one or more probes are incubated with the sample at one or more temperatures between 20 degrees Celsius (°C) to 100°C. In some embodiments, the one or more probes are incubated with the sample at one or more temperatures of at least or up to 20°C, at least or up to 21 °C, at least or up to 22°C, at least or up to 23' ’C, at least or up to 24°C, at le ast or up to 25 °C, at least or up to 26°C, at least or up to 27°C, at least or up to 28°C, at least or up to 29°C, at least or up to 30°C, at least or up to 31 °C, at least or up to 32°C, at least or up to 33 °C, at least or up to 34°C, at least or up to 35°C, at least or up to 36°C, at least or up to 37°C, at least or up to 38°C, at least or up to 39°C, at least or up to 40°C, at least or up to 41 °C, at least or up to 42°C, at least or up to 43°C, at least or up to 44°C, at least or up to 45 °C, at least or up to 46°C, at least or up to 47°C, at least or up to 48 °C, at least or up to 49°C, at least or up to 50°C, at least or up to 51 °C, at least or up to 52°C, at least or up to 53 °C, at least or up to 54°C, at least or up to 55°C, at least or up to 56°C, at least or up to 57°C, at least or up to 58°C, at least or up to 59°C, at least or up to 60°C, at least or up to 61 °C, at least or up to 62°C, at least or up to 63°C, at least or up to 64°C, at least or up to 65 °C, at least or up to 66°C, at least or up to 67°C, at least or up to 68°C, at least or up to 69°C, at least or up to 70°C, at least or up to 71 °C, at least or up to 72°C, at least or up to 73 °C, at least or up to 74°C, at least or up to 75°C, at least or up to 76°C, at least or up to 77°C, at least or up to 78°C, at least or up to 79°C, at least or up to 80°C, at least or up to 81 °C, at least or up to 82°C, at least or up to 83°C, at least or up to 84°C, at least or up to 85 °C, at least or up to 86°C, at least or up to 87°C, at least or up to 88°C, at least or up to 89°C, at least or up to 90°C, at least or up to 91 °C, at least or up to 92°C, at least or up to 93 °C, at least or up toAttorney Ref: 42800-64265 / WO (001WO)94 °C, at least or up to 95°C, at least or up to 96°C, at least or up to 97°C, at least or up to 98°C, at least or up to 99°C, or at least or up to 100°C. In some embodiments, the one or more probes are incubated with the sample at one or more temperatures of 20°C, 21 °C, 22°C, 23 °C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C,51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C,65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71 °C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C,79°C, 80°C, 81 °C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 91 °C, 92°C,93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, or 100°C.

[0169] In some embodiments, each probe of the one or more probes is configured to bind to a sequence specific to the one or more genes. In some embodiments, each probe of the one or more probes is hybridized to the sequence specific to the one or more genes. In some embodiments, each probe of the one or more probes is specific to one gene of the one or more genes. In some embodiments, each probe of the one or more probes is specific to two genes of the one or more genes. In some embodiments, each probe of the one or more probes is specific to at least or up to one gene, at least or up to two genes, at least or up to three genes, at least or up to four genes, at least or up to five genes, at least or up to six genes, at least or up to seven genes, at least or up to eight genes, at least or up to nine genes, or at least or up to ten genes. In some embodiments, each of the one or more target polynucleotides comprises the sequence specific to the one or more genes.

[0170] In some embodiments, the one or more target sequences comprise between one target sequence and 100,000,000 target sequences. In some embodiments, the one or more target sequences comprise at least or up to one target sequence, at least or up to 10 target sequences, at least or up to 20 target sequences, at least or up to 30 target sequences, at least or up to 40 target sequences, at least or up to 50 target sequences, at least or up to 60 target sequences, at least or up to 70 target sequences, at least or up to 80 target sequences, at least or up to 90 target sequences, at least or up to 100 target sequences, at least or up to 200 target sequences, at least or up to 300 target sequences, at least or up to 400 target sequences, at least or up to 500 target sequences, at least or up to 600 target sequences, at least or up to 700 target sequences, at least or up to 800 target sequences, at least or up to 900 target sequences, at least or up to 1 ,000 target sequences, at least or up to 2,000 target sequences, at least or up to 3,000 target sequences, at least or up to 4,000 target sequences, at least or up to 5,000 targetAttorney Ref: 42800-64265 / WO (001WO) sequences, at least or up to 6,000 target sequences, at least or up to 7,000 target sequences, at least or up to 8,000 target sequences, at least or up to 9,000 target sequences, at least or up to 10,000 target sequences, at least or up to 20,000 target sequences, at least or up to 30,000 target sequences, at least or up to 40,000 target sequences, at least or up to 50,000 target sequences, at least or up to 60,000 target sequences, at least or up to 70,000 target sequences, at least or up to 80,000 target sequences, at least or up to 90,000 target sequences, at least or up to 100,000 target sequences, at least or up to 200,000 target sequences, at least or up to 300,000 target sequences, at least or up to 400,000 target sequences, at least or up to 500,000 target sequences, at least or up to 600,000 target sequences, at least or up to 700,000 target sequences, at least or up to 800,000 target sequences, at least or up to 900,000 target sequences, or at least or up to 1,000,000 target sequences.

[0171] In some embodiments, the one or more genes comprise between one gene and 100,000,000 genes. In some embodiments, the one or more genes comprise at least or up to one gene, at least or up to 10 genes, at least or up to 20 genes, at least or up to 30 genes, at least or up to 40 genes, at least or up to 50 genes, at least or up to 60 genes, at least or up to 70 genes, at least or up to 80 genes, at least or up to 90 genes, at least or up to 100 genes, at least or up to 200 genes, at least or up to 300 genes, at least or up to 400 genes, at least or up to 500 genes, at least or up to 600 genes, at least or up to 700 genes, at least or up to 800 genes, at least or up to 900 genes, at least or up to 1,000 genes, at least or up to 2,000 genes, at least or up to 3,000 genes, at least or up to 4,000 genes, at least or up to 5,000 genes, at least or up to 6,000 genes, at least or up to 7,000 genes, at least or up to 8,000 genes, at least or up to 9,000 genes, at least or up to 10,000 genes, at least or up to 20,000 genes, at least or up to 30,000 genes, at least or up to 40,000 genes, at least or up to 50,000 genes, at least or up to 60,000 genes, at least or up to 70,000 genes, at least or up to 80,000 genes, at least or up to 90,000 genes, at least or up to 100,000 genes, at least or up to 200,000 genes, at least or up to 300,000 genes, at least or up to 400,000 genes, at least or up to 500,000 genes, at least or up to 600,000 genes, at least or up to 700,000 genes, at least or up to 800,000 genes, at least or up to 900,000 genes, or at least or up to 1,000,000 genes.

[0172] In some embodiments, the one or more target polynucleotides comprise between one target polynucleotide and 100,000,000 target polynucleotides. In some embodiments, the one or more target polynucleotides comprise at least or up to one target polynucleotide, at least or up to 10 target polynucleotides, at least or up to 20 target polynucleotides, at least or up to 30Attorney Ref: 42800-64265 / WO (001WO) target polynucleotides, at least or up to 40 target polynucleotides, at least or up to 50 target polynucleotides, at least or up to 60 target polynucleotides, at least or up to 70 target polynucleotides, at least or up to 80 target polynucleotides, at least or up to 90 target polynucleotides, at least or up to 100 target polynucleotides, at least or up to 200 target polynucleotides, at least or up to 300 target polynucleotides, at least or up to 400 target polynucleotides, at least or up to 500 target polynucleotides, at least or up to 600 target polynucleotides, at least or up to 700 target polynucleotides, at least or up to 800 target polynucleotides, at least or up to 900 target polynucleotides, at least or up to 1 ,000 target polynucleotides, at least or up to 2,000 target polynucleotides, at least or up to 3,000 target polynucleotides, at least or up to 4,000 target polynucleotides, at least or up to 5,000 target polynucleotides, at least or up to 6,000 target polynucleotides, at least or up to 7,000 target polynucleotides, at least or up to 8,000 target polynucleotides, at least or up to 9,000 target polynucleotides, at least or up to 10,000 target polynucleotides, at least or up to 20,000 target polynucleotides, at least or up to 30,000 target polynucleotides, at least or up to 40,000 target polynucleotides, at least or up to 50,000 target polynucleotides, at least or up to 60,000 target polynucleotides, at least or up to 70,000 target polynucleotides, at least or up to 80,000 target polynucleotides, at least or up to 90,000 target polynucleotides, at least or up to 100,000 target polynucleotides, at least or up to 200,000 target polynucleotides, at least or up to 300,000 target polynucleotides, at least or up to 400,000 target polynucleotides, at least or up to 500,000 target polynucleotides, at least or up to 600,000 target polynucleotides, at least or up to 700,000 target polynucleotides, at least or up to 800,000 target polynucleotides, at least or up to 900,000 target polynucleotides, or at least or up to 1,000,000 target polynucleotides.

[0173] In some embodiments, the one or more target polynucleotides comprise ribonucleic acid (RNA) sequences. In some embodiments, the RNA sequences are one or more messenger RNA (mRNA). In some embodiments, the one or more target polynucleotides comprise deoxyribonucleic acid (DNA) sequences. In some embodiments, the DNA sequences are genomic DNA sequences. In some embodiments, the genomic DNA sequences are nuclear DNA sequences.

[0174] In some embodiments, the one or more target polynucleotides comprise between one target sequence and 100,000,000 target sequences. In some embodiments, the one or more target polynucleotides comprise at least or up to one target sequence, at least or up to 10 target sequences, at least or up to 20 target sequences, at least or up to 30 target sequences, atAttorney Ref: 42800-64265 / WO (001WO) least or up to 40 target sequences, at least or up to 50 target sequences, at least or up to 60 target sequences, at least or up to 70 target sequences, at least or up to 80 target sequences, at least or up to 90 target sequences, at least or up to 100 target sequences, at least or up to 200 target sequences, at least or up to 300 target sequences, at least or up to 400 target sequences, at least or up to 500 target sequences, at least or up to 600 target sequences, at least or up to 700 target sequences, at least or up to 800 target sequences, at least or up to 900 target sequences, at least or up to 1,000 target sequences, at least or up to 2,000 target sequences, at least or up to 3,000 target sequences, at least or up to 4,000 target sequences, at least or up to 5,000 target sequences, at least or up to 6,000 target sequences, at least or up to 7,000 target sequences, at least or up to 8,000 target sequences, at least or up to 9,000 target sequences, at least or up to 10,000 target sequences, at least or up to 20,000 target sequences, at least or up to 30,000 target sequences, at least or up to 40,000 target sequences, at least or up to 50,000 target sequences, at least or up to 60,000 target sequences, at least or up to 70,000 target sequences, at least or up to 80,000 target sequences, at least or up to 90,000 target sequences, at least or up to 100,000 target sequences, at least or up to 200,000 target sequences, at least or up to 300,000 target sequences, at least or up to 400,000 target sequences, at least or up to 500,000 target sequences, at least or up to 600,000 target sequences, at least or up to 700,000 target sequences, at least or up to 800,000 target sequences, at least or up to 900,000 target sequences, or at least or up to 1,000,000 target sequences.

[0175] In some embodiments, the one or more probes comprise nucleic acid. In some embodiments, the nucleic acid is selected from the group consisting of: RNA, DNA 1,5- Anhydrohexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), fluoroarabino nucleic acid (FANA), and any combination thereof. In some embodiments, the one or more probes comprise RNA. In some embodiments, the one or more probes comprise DNA. In some embodiments, the one or more probes comprise single-stranded probes. In some embodiments, the one or more probes comprise double-stranded probes.

[0176] In some embodiments, the one or more probes comprise between 1 nucleotide to 50,000 nucleotides. In some embodiments, one or more probes comprise at least or up to 1 nucleotide, at least or up to 2 nucleotides, at least or up to 3 nucleotides, at least or up to 4 nucleotides, at least or up to 5 nucleotides, at least or up to 6 nucleotides, at least or up to 7 nucleotides, at least or up to 8 nucleotides, at least or up to 9 nucleotides, at least or up to 10Attorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 11 nucleotides, at least or up to 12 nucleotides, at least or up to 13 nucleotides, at least or up to 14 nucleotides, at least or up to 15 nucleotides, at least or up to 16 nucleotides, at least or up to 17 nucleotides, at least or up to 18 nucleotides, at least or up to 19 nucleotides, at least or up to 20 nucleotides, at least or up to 21 nucleotides, at least or up to 22 nucleotides, at least or up to 23 nucleotides, at least or up to 24 nucleotides, at least or up to 25 nucleotides, at least or up to 26 nucleotides, at least or up to 27 nucleotides, at least or up to 28 nucleotides, at least or up to 29 nucleotides, at least or up to 30 nucleotides, at least or up to 31 nucleotides, at least or up to 32 nucleotides, at least or up to 33 nucleotides, at least or up to 34 nucleotides, at least or up to 35 nucleotides, at least or up to 36 nucleotides, at least or up to 37 nucleotides, at least or up to 38 nucleotides, at least or up to 39 nucleotides, at least or up to 40 nucleotides, at least or up to 41 nucleotides, at least or up to 42 nucleotides, at least or up to 43 nucleotides, at least or up to 44 nucleotides, at least or up to 45 nucleotides, at least or up to 46 nucleotides, at least or up to 47 nucleotides, at least or up to 48 nucleotides, at least or up to 49 nucleotides, at least or up to 50 nucleotides, at least or up to 51 nucleotides, at least or up to 52 nucleotides, at least or up to 53 nucleotides, at least or up to 54 nucleotides, at least or up to 55 nucleotides, at least or up to 56 nucleotides, at least or up to 57 nucleotides, at least or up to 58 nucleotides, at least or up to 59 nucleotides, at least or up to 60 nucleotides, at least or up to 61 nucleotides, at least or up to 62 nucleotides, at least or up to 63 nucleotides, at least or up to 64 nucleotides, at least or up to 65 nucleotides, at least or up to 66 nucleotides, at least or up to 67 nucleotides, at least or up to 68 nucleotides, at least or up to 69 nucleotides, at least or up to 70 nucleotides, at least or up to 71 nucleotides, at least or up to 72 nucleotides, at least or up to 73 nucleotides, at least or up to 74 nucleotides, at least or up to 75 nucleotides, at least or up to 76 nucleotides, at least or up to 77 nucleotides, at least or up to 78 nucleotides, at least or up to 79 nucleotides, at least or up to 80 nucleotides, at least or up to 81 nucleotides, at least or up to 82 nucleotides, at least or up to 83 nucleotides, at least or up to 84 nucleotides, at least or up to 85 nucleotides, at least or up to 86 nucleotides, at least or up to 87 nucleotides, at least or up to 88 nucleotides, at least or up to 89 nucleotides, at least or up to 90 nucleotides, at least or up to 91 nucleotides, at least or up to 92 nucleotides, at least or up to 93 nucleotides, at least or up to 94 nucleotides, at least or up to 95 nucleotides, at least or up to 96 nucleotides, at least or up to 97 nucleotides, at least or up to 98 nucleotides, at least or up to 99 nucleotides, at least or up to 100 nucleotides, at least or up to 101 nucleotides, at least or up to 102 nucleotides, at least or up to 103 nucleotides, at least or up to 104 nucleotides, at least or up to 105 nucleotides, at least or up to 106 nucleotides, at least or upAttorney Ref: 42800-64265 / WO (001WO) to 107 nucleotides, at least or up to 108 nucleotides, at least or up to 109 nucleotides, at least or up to 110 nucleotides, at least or up to 111 nucleotides, at least or up to 112 nucleotides, at least or up to 1 13 nucleotides, at least or up to 1 14 nucleotides, at least or up to 115 nucleotides, at least or up to 116 nucleotides, at least or up to 117 nucleotides, at least or up to 118 nucleotides, at least or up to 119 nucleotides, at least or up to 120 nucleotides, at least or up to 121 nucleotides, at least or up to 122 nucleotides, at least or up to 123 nucleotides, at least or up to 124 nucleotides, at least or up to 125 nucleotides, at least or up to 126 nucleotides, at least or up to 127 nucleotides, at least or up to 128 nucleotides, at least or up to 129 nucleotides, at least or up to 130 nucleotides, at least or up to 131 nucleotides, at least or up to 132 nucleotides, at least or up to 133 nucleotides, at least or up to 134 nucleotides, at least or up to 135 nucleotides, at least or up to 136 nucleotides, at least or up to 137 nucleotides, at least or up to 138 nucleotides, at least or up to 139 nucleotides, at least or up to 140 nucleotides, at least or up to 141 nucleotides, at least or up to 142 nucleotides, at least or up to 143 nucleotides, at least or up to 144 nucleotides, at least or up to 145 nucleotides, at least or up to 146 nucleotides, at least or up to 147 nucleotides, at least or up to 148 nucleotides, at least or up to 149 nucleotides, at least or up to 150 nucleotides, at least or up to 200 nucleotides, at least or up to 250 nucleotides, at least or up to 300 nucleotides, at least or up to 350 nucleotides, at least or up to 400 nucleotides, at least or up to 450 nucleotides, at least or up to 500 nucleotides, at least or up to 550 nucleotides, at least or up to 600 nucleotides, at least or up to 650 nucleotides, at least or up to 700 nucleotides, at least or up to 750 nucleotides, at least or up to 800 nucleotides, at least or up to 850 nucleotides, at least or up to 900 nucleotides, at least or up to 950 nucleotides, at least or up to 1 ,000 nucleotides, at least or up to 1,500 nucleotides, at least or up to 2,000 nucleotides, at least or up to 2,500 nucleotides, at least or up to 3,000 nucleotides, at least or up to 3,500 nucleotides, at least or up to 4,000 nucleotides, at least or up to 4,500 nucleotides, at least or up to 5,000 nucleotides, at least or up to 5,500 nucleotides, at least or up to 6,000 nucleotides, at least or up to 6,500 nucleotides, at least or up to 7,000 nucleotides, at least or up to 7,500 nucleotides, at least or up to 8,000 nucleotides, at least or up to 8,500 nucleotides, at least or up to 9,000 nucleotides, at least or up to 9,500 nucleotides, at least or up to 10,000 nucleotides, at least or up to 10,500 nucleotides, at least or up to 11,000 nucleotides, at least or up to 11 ,500 nucleotides, at least or up to 12,000 nucleotides, at least or up to 12,500 nucleotides, at least or up to 13,000 nucleotides, at least or up to 14,000 nucleotides, at least or up to 15,000 nucleotides, at least or up to 16,000 nucleotides, at least or up to 17,000 nucleotides, at least or up to 18,000 nucleotides, at least or up to 19,000Attorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 20,000 nucleotides, at least or up to 21,000 nucleotides, at least or up to 22,000 nucleotides, at least or up to 23,000 nucleotides, at least or up to 24,000 nucleotides, at least or up to 25,000 nucleotides, at least or up to 26,000 nucleotides, at least or up to 27,000 nucleotides, at least or up to 28,000 nucleotides, at least or up to 29,000 nucleotides, at least or up to 30,000 nucleotides, at least or up to 31,000 nucleotides, at least or up to 32,000 nucleotides, at least or up to 33,000 nucleotides, at least or up to 34,000 nucleotides, at least or up to 35,000 nucleotides, at least or up to 36,000 nucleotides, at least or up to 37,000 nucleotides, at least or up to 38,000 nucleotides, at least or up to 39,000 nucleotides, at least or up to 40,000 nucleotides, at least or up to 41,000 nucleotides, at least or up to 42,000 nucleotides, at least or up to 43,000 nucleotides, at least or up to 44,000 nucleotides, at least or up to 45,000 nucleotides, at least or up to 46,000 nucleotides, at least or up to 47,000 nucleotides, at least or up to 48,000 nucleotides, at least or up to 49,000 nucleotides, or at least or up to 50,000 nucleotides. In some embodiments, the one or more probes comprise 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides, 41 nucleotides, 42 nucleotides, 43 nucleotides, 44 nucleotides, 45 nucleotides, 46 nucleotides, 47 nucleotides, 48 nucleotides, 49 nucleotides, 50 nucleotides,51 nucleotides, 52 nucleotides, 53 nucleotides, 54 nucleotides, 55 nucleotides, 56 nucleotides, 57 nucleotides, 58 nucleotides, 59 nucleotides, 60 nucleotides, 61 nucleotides,62 nucleotides, 63 nucleotides, 64 nucleotides, 65 nucleotides, 66 nucleotides, 67 nucleotides, 68 nucleotides, 69 nucleotides, 70 nucleotides, 71 nucleotides, 72 nucleotides,73 nucleotides, 74 nucleotides, 75 nucleotides, 76 nucleotides, 77 nucleotides, 78 nucleotides, 79 nucleotides, 80 nucleotides, 81 nucleotides, 82 nucleotides, 83 nucleotides,84 nucleotides, 85 nucleotides, 86 nucleotides, 87 nucleotides, 88 nucleotides, 89 nucleotides, 90 nucleotides, 91 nucleotides, 92 nucleotides, 93 nucleotides, 94 nucleotides,95 nucleotides, 96 nucleotides, 97 nucleotides, 98 nucleotides, 99 nucleotides, 100 nucleotides, 101 nucleotides, 102 nucleotides, 103 nucleotides, 104 nucleotides, 105 nucleotides, 106 nucleotides, 107 nucleotides, 108 nucleotides, 109 nucleotides, 110 nucleotides, 111 nucleotides, 112 nucleotides, 113 nucleotides, 114 nucleotides, 115Attorney Ref: 42800-64265 / WO (001WO) nucleotides, 116 nucleotides , 117 nucleotides , 118 nucleotides, 119 nucleotides, 120 nucleotides, 121 nucleotides, 122 nucleotides, 123 nucleotides, 124 nucleotides, 125 nucleotides, 126 nucleotides, 127 nucleotides, 128 nucleotides, 129 nucleotides, 130 nucleotides, 131 nucleotides, 132 nucleotides, 133 nucleotides, 134 nucleotides, 135 nucleotides, 136 nucleotides, 137 nucleotides, 138 nucleotides, 139 nucleotides, 140 nucleotides, 141 nucleotides, 142 nucleotides, 143 nucleotides, 144 nucleotides, 145 nucleotides, 146 nucleotides, 147 nucleotides, 148 nucleotides, 149 nucleotides, 150 nucleotides, 200 nucleotides, 250 nucleotides, 300 nucleotides, 350 nucleotides, 400 nucleotides, 450 nucleotides, 500 nucleotides, 550 nucleotides, 600 nucleotides, 650 nucleotides, 700 nucleotides, 750 nucleotides, 800 nucleotides, 850 nucleotides, 900 nucleotides, 950 nucleotides, 1,000 nucleotides, 1,500 nucleotides, 2,000 nucleotides,2,500 nucleotides, 3,000 nucleotides, 3,500 nucleotides, 4,000 nucleotides, 4,500 nucleotides, 5,000 nucleotides, 5,500 nucleotides, 6,000 nucleotides, 6,500 nucleotides,7,000 nucleotides, 7,500 nucleotides, 8,000 nucleotides, 8,500 nucleotides, 9,000 nucleotides, 9,500 nucleotides, 10,000 nucleotides, 10,500 nucleotides, 11,000 nucleotides,11,500 nucleotides, 12,000 nucleotides, 12,500 nucleotides, 13,000 nucleotides, 14,000 nucleotides, 15,000 nucleotides, 16,000 nucleotides, 17,000 nucleotides, 18,000 nucleotides, 19,000 nucleotides, 20,000 nucleotides, 21,000 nucleotides, 22,000 nucleotides, 23,000 nucleotides, 24,000 nucleotides, 25,000 nucleotides, 26,000 nucleotides, 27,000 nucleotides, 28,000 nucleotides, 29,000 nucleotides, 30,000 nucleotides, 31,000 nucleotides, 32,000 nucleotides, 33,000 nucleotides, 34,000 nucleotides, 35,000 nucleotides, 36,000 nucleotides, 37,000 nucleotides, 38,000 nucleotides, 39,000 nucleotides, 40,000 nucleotides, 41,000 nucleotides, 42,000 nucleotides, 43,000 nucleotides, 44,000 nucleotides, 45,000 nucleotides, 46,000 nucleotides, 47,000 nucleotides, 48,000 nucleotides, 49,000 nucleotides, or 50,000 nucleotides. In some embodiments, each probe of the one or more probes comprises 120 nucleotides to 7,000 nucleotides. In some embodiments, each probe of the one or more probes comprises 200 nucleotides to 5,000 nucleotides. In some embodiments, each probe of the one or more probes comprises 500 nucleotides to 3,000 nucleotides. In some embodiments, each probe of the one or more probes comprises 1,000 nucleotides to 3,000 nucleotides.

[0177] In some embodiments, the one or more probes comprise one or more modified nucleotides. Modified nucleotides refer to any nucleotide that is not adenine (A), guanine (G),Attorney Ref: 42800-64265 / WO (001WO) thymine (T), cytosine (C), or uracil (U). In some embodiments, the one or more probes comprise natural nucleotides.

[0178] In some embodiments, the one or more modified nucleotides are selected from the group consisting of: 2-amino-deoxyadenosine, 2’-dInosine, 2’-dUridine, 2-thio-dT, 4-thio-dT, 4-thio-uridine, 5-Br-dC, 5-Br-dU, 5-Br-U, t-ethynyl-dU, 5-F-dU, 5-formyl-dC, 5- hydroxymethyl-dC, 5-hydroxymethyl-dU, 5-I-dC, 5-I-dU, 5-Iod-C, 5-Iod-U, 5-Me-C, 5- methyl-deoxycytidine, 5-trifluormethyl-dU, 8-oxo-dG, aminoethyl-phenox azinedeoxycytidine, C-5 propynyl-deoxycytidine, C-5 propynyl deoxyuridine, C8-alkyne-dC, C8- alkyene-dU, dimethyl-2’ -deoxy adenosine, formylindole, inosine, inverted end, iso-dC, iso- dG, Nl-methyl-pseudouridine, N4-ethyl-dC, N6,N6-dimethyl-rA, N6-Me-A, N6-Me-dA, N- POM caged-dT, perylene-dU, pseudouridine, biotinylated nucleotides, and any combination thereof. In some embodiments, the one or more probes comprise between 0 modified nucleotides to 50 modified nucleotides. In some embodiments, the one or more probes comprise at least or up to 0 modified nucleotides, at least or up to 1 modified nucleotide, at least or up to 2 modified nucleotides, at least or up to 3 modified nucleotides, at least or up to 4 modified nucleotides, at least or up to 5 modified nucleotides, at least or up to 6 modified nucleotides, at least or up to 7 modified nucleotides, at least or up to 8 modified nucleotides, at least or up to 9 modified nucleotides, at least or up to 10 modified nucleotides, at least or up to 11 modified nucleotides, at least or up to 12 modified nucleotides, at least or up to 13 modified nucleotides, at least or up to 14 modified nucleotides, at least or up to 15 modified nucleotides, at least or up to 16 modified nucleotides, at least or up to 17 modified nucleotides, at least or up to 18 modified nucleotides, at least or up to 19 modified nucleotides, at least or up to 20 modified nucleotides, at least or up to 21 modified nucleotides, at least or up to 22 modified nucleotides, at least or up to 23 modified nucleotides, at least or up to 24 modified nucleotides, at least or up to 25 modified nucleotides, at least or up to 26 modified nucleotides, at least or up to 27 modified nucleotides, at least or up to 28 modified nucleotides, at least or up to 29 modified nucleotides, at least or up to 30 modified nucleotides, at least or up to 31 modified nucleotides, at least or up to 32 modified nucleotides, at least or up to 33 modified nucleotides, at least or up to 34 modified nucleotides, at least or up to 35 modified nucleotides, at least or up to 36 modified nucleotides, at least or up to 37 modified nucleotides, at least or up to 38 modified nucleotides, at least or up to 39 modified nucleotides, at least or up to 40 modifiedAttorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 41 modified nucleotides, at least or up to 42 modified nucleotides, at least or up to 43 modified nucleotides, at least or up to 44 modified nucleotides, at least or up to 45 modified nucleotides, at least or up to 46 modified nucleotides, at least or up to 47 modified nucleotides, at least or up to 48 modified nucleotides, at least or up to 49 modified nucleotides, or at least or up to 50 modified nucleotides. In some embodiments, the one or more probes comprise 0 modified nucleotides, 1 modified nucleotides, 2 modified nucleotides, 3 modified nucleotides, 4 modified nucleotides, 5 modified nucleotides, 6 modified nucleotides, 7 modified nucleotides, 8 modified nucleotides, 9 modified nucleotides, 10 modified nucleotides, 11 modified nucleotides, 12 modified nucleotides, 13 modified nucleotides, 14 modified nucleotides, 15 modified nucleotides, 16 modified nucleotides, 17 modified nucleotides, 18 modified nucleotides, 19 modified nucleotides, 20 modified nucleotides, 21 modified nucleotides, 22 modified nucleotides, 23 modified nucleotides, 24 modified nucleotides, 25 modified nucleotides, 26 modified nucleotides, 27 modified nucleotides, 28 modified nucleotides, 29 modified nucleotides, 30 modified nucleotides, 31 modified nucleotides, 32 modified nucleotides, 33 modified nucleotides, 34 modified nucleotides, 35 modified nucleotides, 36 modified nucleotides, 37 modified nucleotides, 38 modified nucleotides, 39 modified nucleotides, 40 modified nucleotides, 41 modified nucleotides, 42 modified nucleotides, 43 modified nucleotides, 44 modified nucleotides, 45 modified nucleotides, 46 modified nucleotides, 47 modified nucleotides, 48 modified nucleotides, 49 modified nucleotides, or50 modified nucleotides.

[0179] Alternatively, in some embodiments, the one or more probes may not comprise one or more modified nucleotides.

[0180] In some embodiments, the one or more probes comprise between one probe to 50,000 probes. In some embodiments, the one or more probes comprise at least or up to one probe, at least or up to lO probes, at least or up to 50 probes, at least or up to lOO probes, at least or up to 500 probes, at least or up to 1 ,000 probes, at least or up to 2,000 probes, at least or up to 3,000 probes, at least or up to 4,000 probes, at least or up to 5,000 probes, at least or up to 6,000 probes, at least or up to 7,000 probes, at least or up to 8,000 probes, at least or up to 9,000 probes, at least or up to 10,000 probes, at least or up to 20,000 probes, at least or up 25,000 probes, at least or up to 30,000 probes, at least or up to 35,000 probes,Attorney Ref: 42800-64265 / WO (001WO) at least or up to 40,000 probes, at least or up to 45,000 probes, or at least or up to 50,000 probes.

[0181] In some embodiments, the one or more probes comprise one or more nucleotide sequences selected from the group consisting of: SEQ ID NOs: 22-578, and any combination thereof. In some embodiments, the one or more probes have a sequence identity of between 0% to 100% to one or more nucleotide sequences selected from the group consisting of: SEQ ID NOs: 22-578, and any combination thereof. In some embodiments, the one or more probes have a sequence identity of at least or up to 0%, at least or up to 5%, at least or up to 10%, at least or up to 15%, at least or up to 20%, at least or up to 25%, at least or up to 30%, at least or up to 35%, at least or up to 40%, at least or up to 45%, at least or up to 50%, at least or up to 55%, at least or up to 60%, at least or up to 65%, at least or up to 70%, at least or up to 75%, at least or up to 80%, at least or up to 85%, at least or up to 90%, at least or up to 95%, at least or up to 96%, at least or up to 97%, at least or up to 98%, at least or up to 99%, at least or up to 99.5%, at least or up to 99.8%, at least or up to 99.9%, or at least or up to 100% to one or more nucleotide sequences selected from the group consisting of: SEQ ID NOs: 22-578, and any combination thereof.

[0182] In some embodiments, the one or more target sequences comprise between one target sequence and 100,000,000 target sequences. In some embodiments, the one or more target sequences comprise at least or up to one target sequence, at least or up to 10 target sequences, at least or up to 20 target sequences, at least or up to 30 target sequences, at least or up to 40 target sequences, at least or up to 50 target sequences, at least or up to 60 target sequences, at least or up to 70 target sequences, at least or up to 80 target sequences, at least or up to 90 target sequences, at least or up to 100 target sequences, at least or up to 200 target sequences, at least or up to 300 target sequences, at least or up to 400 target sequences, at least or up to 500 target sequences, at least or up to 600 target sequences, at least or up to 700 target sequences, at least or up to 800 target sequences, at least or up to 900 target sequences, at least or up to 1,000 target sequences, at least or up to 2,000 target sequences, at least or up to 3,000 target sequences, at least or up to 4,000 target sequences, at least or up to 5,000 target sequences, at least or up to 6,000 target sequences, at least or up to 7,000 target sequences, at least or up to 8,000 target sequences, at least or up to 9,000 target sequences, at least or up to 10,000 target sequences, at least or up to 20,000 target sequences, at least or up to 30,000 target sequences, at least or up to 40,000 targetAttorney Ref: 42800-64265 / WO (001WO) sequences, at least or up to 50,000 target sequences, at least or up to 60,000 target sequences, at least or up to 70,000 target sequences, at least or up to 80,000 target sequences, at least or up to 90,000 target sequences, at least or up to 100,000 target sequences, at least or up to 200,000 target sequences, at least or up to 300,000 target sequences, at least or up to 400,000 target sequences, at least or up to 500,000 target sequences, at least or up to 600,000 target sequences, at least or up to 700,000 target sequences, at least or up to 800,000 target sequences, at least or up to 900,000 target sequences, or at least or up to 1 ,000,000 target sequences.

[0183] In some embodiments, the one or more target sequences comprise an exon sequence. In some embodiments, the one or more target sequences comprise an intron sequence. In some embodiments, the one or more target sequences comprise a conserved region of the one or more genes. A conserved region of the one or more genes can refer to a region of the one or more genes where the sequence of the region has remains unchanged or similar in sequence throughout evolution. In some embodiments, the conserved region of the one or more genes is identified from a reference genome. In some embodiments, the one or more probes hybridize with the conserved region of the one or more genes.

[0184] In some embodiments, the one or more probes are coupled to a ligand. In some embodiments, the ligand is selected from the group consisting of: biotin, polyethylene glycol, protein A, an amine ligand, a sulfhydryl ligand, an aldehyde group ligand, a carboxyl ligand, and any combination thereof. In some embodiments, the ligand is biotin. In some embodiments, the ligand is coupled to a 5’ end of the one or more probes. In some embodiments, the ligand is coupled to a 3’ end of the one or more probes. In some embodiments, the ligand is coupled to the 5’ end and the 3’ end of the one or more probes. In some embodiments, the one or more probes are coupled to the ligand via a covalent bond. In some embodiments, the covalent bond is a polar covalent bond or a non-polar covalent bond. In some embodiments, the one or more probes are coupled to ligand via a non-covalent bond. Non-limiting examples of non-covalent bonds include hydrogen bonds, hydrophobic interactions, halogen bonding, van der Waals forces, London dispersion interactions, electrostatic interactions, ionic bonds, or any combination thereof.

[0185] In some embodiments, the step of generating the sequence information further comprises enriching the one or more target polynucleotides hybridized with the one or more probes from the sample. In some embodiments, the enriching the one or more targetAttorney Ref: 42800-64265 / WO (001WO) polynucleotides hybridized with the one or more probes from the sample separates the one or more target polynucleotides from the non-target polynucleotides. In some embodiments, the enriching removes the one or more target polynucleotides from the sample. In some embodiments, the enriching removes the non-target polynucleotides from the sample. In some embodiments, the enriching step is performed by reacting the one or more probes with a bead and isolating the bead. In some embodiments, the reacting the one or more probes with a bead comprises incubating the one or more target polynucleotides hybridized with the one or more probes with the bead. In some embodiments, the enriching step generates enriched polynucleotides. In some embodiments, the enriched polynucleotides comprise the one or more target polynucleotides.

[0186] In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead for between 0 minutes to 3 hours. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead for at least or up to 0 minutes, at least or up to 15 minutes, at least or up to 30 minutes, at least or up to 45 minutes, at least or up to 60 minutes, at least or up to 75 minutes, at least or up to 90 minutes, at least or up to 105 minutes, at least or up to 120 minutes, at least or up to 135 minutes, at least or up to 150 minutes, at least or up to 165 minutes, or at least or up to 180 minutes. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead for 0 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 135 minutes, 150 minutes, 165 minutes, or 180 minutes. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead at a temperature between 15°C to 35°C. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead at a temperature of at least or up to 15 °C, at least or up to 16°C, at least or up to 17 °C, at least or up to 18°C, at least or up to 19°C, at least or up to 20°C, at least or up to 21 °C, at least or up to 22°C, at least or up to 23°C, at least or up to 24°C, at least or up to 25 °C, at least or up to 26°C, at least or up to 27 °C, at least or up to 28 °C, at least or up to 29°C, at least or up to 30°C, at least or up to 31 °C, at least or up to 32°C, at least or up to33°C, at least or up to 34°C, or at least or up to 35°C. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are incubated with the bead at a temperature of 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27 °C, 28 °C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, or 35°C.Attorney Ref: 42800-64265 / WO (001WO)

[0187] In some embodiments, the isolating the bead obtains enriched target polynucleotides. In some embodiments, the bead is configured to couple to the one or more probes hybridized with the one or more target polynucleotides. In some embodiments, the bead is configured to bind to the one or more probes. In some embodiments, the bead is coupled to a binding partner. In some embodiments, the binding partner is configured to couple to the ligand on the one or more probes. In some embodiments, the binding partner couples to the ligand via a non-covalent bond. In some embodiments, the binding partner couples to the ligand via a covalent bond. In some embodiments, the covalent bond is a polar covalent bond or a non- polar covalent bond. Non-limiting examples of non-covalent bonds include hydrogen bonds, hydrophobic interactions, halogen bonding, van der Waals forces, London dispersion interactions, electrostatic interactions, ionic bonds, or any combination thereof. In some embodiments, the binding partner is selected from the group consisting of: streptavidin, cyanate ester, N-hydroxysuccinimide ester, azlactone ring, an aldehyde binding partner, carbonyl diimidazole, protein G, maleimide, SulfoLink, hydrazide, diaminodipropylamine, and any combination thereof. In some embodiments, the binding partner is streptavidin. In some embodiments, one probe of the one or more probes couples to the bead. In some embodiments, more than one probe of the one or more probes couples to the bead. In some embodiments, at least or up to one probe, at least or up to 5 probes, at least or up to 10 probes, at least or up to 20 probes, at least or up to 30 probes, at least or up to 40 probes, at least or up to 50 probes, at least or up to 60 probes, at least or up to 70 probes, at least or up to 80 probes, at least or up to 90 probes, at least or up to 100 probes, at least or up to 200 probes, at least or up to 300 probes, at least or up to 400 probes, at least or up to 500 probes, at least or up to 600 probes, at least or up to 700 probes, at least or up to 800 probes, at least or up to 900 probes, at least or up to 1 ,000 probes, at least or up to 5,000 probes, at least or up to 10,000 probes, at least or up to 50,000 probes, or at least or up to 100,000 probes couples to the bead.

[0188] In some embodiments, the bead is selected from the group consisting of: a metal bead, a glass bead, a plastic bead, a silica bead, a ceramic bead, and any combination thereof. In some embodiments, the bead is a metal bead. In some embodiments, the metal bead is a magnetic bead. In some embodiments, the magnetic bead is a magnetic streptavidin bead.

[0189] Alternatively, in some embodiments, the one or more polynucleotides hybridized with the one or more probes are enriched from the sample using a column. Tn some embodiments,Attorney Ref: 42800-64265 / WO (OOIWO) the column is coupled to the binding partner. In some embodiments, the sample is passed through the column and the one or more probes couple to the binding partner as the sample passes through the column.

[0190] In some embodiments, the step of generating the sequence information further comprises amplifying the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are amplified. In some embodiments, the one or more target polynucleotides are used as a template to extend one or more pairs of universal primers hybridized to the one or more target polynucleotides. In some embodiments, the enriched target polynucleotides are amplified. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides are amplified via one or more of the amplification methods selected from the group consisting of: isothermal amplification, loop mediated isothermal amplification, nucleic acid sequence-based amplification strand displacement amplification, polymerase chain reaction, quantitative polymerase chain reaction (qPCR), ligase chain reaction, rolling circle amplification, helicase dependent amplification, and any combination thereof. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides are amplified via polymerase chain reaction (PCR). In some embodiments, the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides are amplified vis qPCR.

[0191] In some embodiments, qPCR is performed with one or more probes configured to bind to one or more target polynucleotides with one or more mutations. The probes or the primers can be specifically designed to differentiate target polynucleotides with or without a mutation. In some embodiments, the probes or the primers are conjugated to a dye, optionally a fluorescent dye. In some embodiments, the probes or the primers are conjugated to a fluorescent dye and a quencher. In some embodiments, the probes and primers are used dyebased qPCR or probe-based qPCR to detect presence, absence, or relative abundance of mutation.

[0192] In some embodiments, the one or more target polynucleotides or the enriched polynucleotides are amplified via a polymerase. In some embodiments, the polymerase is an RNA polymerase. Non-limiting examples of RNA polymerases include RNA polymerase I, RNA polymerase II, RNA polymerase III, RNA polymerase IV, RNA polymerase V, T7Attorney Ref: 42800-64265 / WO (OOIWO)RNA polymerase, SP6 RNA polymerase, or any combination thereof. In some embodiments, the polymerase is a DNA polymerase. Non-limiting examples of DNA polymerases include DNA polymerase I, DNA polymerase II, Taq polymerase Pfu DNA polymerase, reverse transcriptase, DNA polymerase III, T4 DNA polymerase, DNA polymerase IV, DNA polymerase V, Polymerase a, Polymerase p, Polymerase y, Polymerase X, Polymerase o, Taq DNA polymerase, or any combination thereof. In some embodiments, the polymerase is a high-fidelity polymerase. In some embodiments, the polymerase is Taq DNA polymerase.

[0193] In some embodiments, the step of generating the sequence information further comprises amplifying the one or more polynucleotides prior to the contacting the sample with the one or more probes. In some embodiments, the one or more polynucleotides are amplified via any of the amplification methods disclosed herein.

[0194] Alternatively, in some embodiments, the step of generating the sequence information comprises contacting the sample with one or more pairs of primers. In some embodiments, each pair of primers of the one or more pairs of primers comprises two primers. In some embodiments, the contacting the sample with the one or more pairs of primers induces hybridization of the one or more target polynucleotides with the one or more pairs of primers. In some embodiments, a primer from the one or more pairs of primers hybridizes with a sequence at a 5’ end of the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridizes with a sequence at a 3’ end of the one or more genes. In some embodiments, a first primer of the one or more pairs of primers hybridizes with a first sequence at a 5’ end of the one or more genes and a second primer of the one or more pairs of primers hybridizes with a second sequence at a 3’ end of the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridize with a target sequence at a 5’ end of the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridize with a target sequence at a 3 ’ end of the one or more genes. In some embodiments, a first primer of the one or more pairs of primers hybridizes with a first target sequence at a 5 ’ end of the one or more genes and a second primer of the one or more pairs of primers hybridizes with a second target sequence at the 3 ’ end of the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridizes with a sequence upstream (e.g., 5’) of the one or more mutations in the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridizes with a sequence downstream (e.g., 3) of the one or more mutations in the one or more genes.Attorney Ref: 42800-64265 / WO (OOIWO)In some embodiments, a first primer of the one or more pairs of primers hybridizes with a first sequence 5’ of the one or more mutations in the one or more genes and a second primer of the one or more pairs of primers hybridize with a second sequence 3 ’ of the one or more mutations in the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridizes with a target sequence 5 ’ of the one or more mutations in the one or more genes. In some embodiments, a primer from the one or more pairs of primers hybridizes with a target sequence 3’ of the one or more mutations in the one or more genes. In some embodiments, a first primer of the one or more pairs of primers hybridizes with a first target sequence 5 ’ of the one or more mutations in the one or more genes and a second primer of the one or more pairs of primers hybridize with a second target sequence of the 3’ of the one or more mutations in the one or more genes. In some embodiments, the one or more pairs of primers hybridize with one or more target sequences in the one or more genes. In some embodiments, the one or more pairs of primers hybridize with the one or more mutations in the one or more genes.

[0195] In some embodiments, the one or more pairs of primers hybridize with a conserved region of the one or more genes. In some embodiments, the one or more pairs of primers hybridize with a non-conserved region of the one or more genes. In some embodiments, the non-conserved region of the one or more genes comprises the one or more mutations. In some embodiments, the non-conserved region of the one or more genes comprises a variable region of the one or more genes. In some embodiments, the variable region of the one or more genes can be a region that varies between one subject and another subject.

[0196] In some embodiments, the contacting the sample with the one or more pairs of primers comprises amplifying the one or more target polynucleotides via the one or more pairs of primers. In some embodiments, the region of the one or more target polynucleotides between the first primer of the one or more pairs of primers and the second primer of the one or more pairs of primers is amplified. In some embodiments, the one or more pairs of primers are extended using the one or more target polynucleotides as a template to amplify at least one portion of the one or more target polynucleotides. In some embodiments, the at least one portion of the one or more target polynucleotides comprise the one or more genes. In some embodiments, the at least one portion of the one or more target polynucleotides comprises a target sequence of the one or more genes. In some embodiments, the at least one portion of the one or more target polynucleotides comprises the one or more mutations in the one orAttorney Ref: 42800-64265 / WO (001WO) more genes. In some embodiments, the one or more target polynucleotides are amplified via one or more amplification methods selected from the group consisting of: isothermal amplification, loop mediated isothermal amplification, nucleic acid sequence-based amplification strand displacement amplification, polymerase chain reaction, qPCR, ligase chain reaction, rolling circle amplification, helicase dependent amplification, and any combination thereof. In some embodiments, the one or more target polynucleotides are amplified via polymerase chain reaction (PCR). In some embodiments, the one or more target polynucleotides are amplified via qPCR. In some embodiments, the amplifying the one or more target polynucleotides generates amplified target polynucleotides. In some embodiments, the amplified target polynucleotides comprise the one or more mutations in the one or more genes. In some embodiments, each of the one or more pairs of primers is configured to amplify the one or more target polynucleotides that comprise the one or more mutations in the one or more genes.

[0197] In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides for between 0 minutes to 12 hours. In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides for at least or up to 0 minutes, at least or up to 1 minute, at least or up to 5 minutes, at least or up to10 minutes, at least or up to 15 minutes, at least or up to 20 minutes, at least or up to 25 minutes, at least or up to 30 minutes, at least or up to 35 minutes, at least or up to 40 minutes, at least or up to 45 minutes, at least or up to 50 minutes, at least or up to 55 minutes, at least or up to 60 minutes, at least or up to 75 minutes, at least or up to 90 minutes, at least or up to 105 minutes, at least or up to 120 minutes, at least or up to 135 minutes, at least or up to 150 minutes, at least or up to 165 minutes, at least or up to 3 hours, at least or up to 4 hours, at least or up to 5 hours, at least or up to 6 hours, at least or up to 7 hours, at least or up to 8 hours, at least or up to 9 hours, at least or up to 10 hours, at least or up to 11 hours, or at least or up to 12 hours. In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides for 0 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 120 minutes, 135 minutes, 150 minutes, 165 minutes, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours,11 hours, or 12 hours.Attorney Ref: 42800-64265 / WO (OOIWO)

[0198] In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides at one or more temperatures. In some embodiments, one or more temperatures comprise at least or up to one temperature, at least or up to two temperatures, at least or up to three temperatures, at least or up to four temperatures, at least or up to five temperatures, at least or up to six temperatures, at least or up to seven temperatures, at least or up to eight temperatures, at least or up to nine temperatures, or at least or up to ten temperatures. In some embodiments, the one or more temperatures comprise one temperature, two temperatures, three temperatures, four temperatures, five temperatures, six temperatures, seven temperatures, eight temperatures, nine temperatures, or ten temperatures.

[0199] In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides at one or more temperatures between 0 degrees Celsius (°C) to 100°C. In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides at one or more temperatures of at least or up to 0°C, at least or up to 1 °C, at least or up to 2°C, at least or up to 3°C, at least or up to 4°C, at least or up to 5°C, at least or up to 6°C, at least or up to 7°C, at least or up to 8°C, at least or up to 9°C, at least or up to 10°C, at least or up to 11°C, at least or up to 12°C, at least or up to 13°C, at least or up to 14°C, at least or up to 15°C, at least or up to 16°C, at least or up to 17°C, at least or up to 18°C, at least or up to 19°C, at least or up to 20°C, at least or up to 21 °C, at least or up to22°C, at least or up to 23°C, at least or up to 24°C, at least or up to 25°C, at least or up to26°C, at least or up to 27°C, at least or up to 28°C, at least or up to 29°C, at least or up to30°C, at least or up to 31 °C, at least or up to 32°C, at least or up to 33°C, at least or up to34°C, at least or up to 35°C, at least or up to 36°C, at least or up to 37°C, at least or up to38°C, at least or up to 39°C, at least or up to 40°C, at least or up to 41 °C, at least or up to42°C, at least or up to 43°C, at least or up to 44°C, at least or up to 45°C, at least or up to46°C, at least or up to 47°C, at least or up to 48°C, at least or up to 49°C, at least or up to50°C, at least or up to 51°C, at least or up to 52°C, at least or up to 53°C, at least or up to54°C, at least or up to 55°C, at least or up to 56°C, at least or up to 57°C, at least or up to58°C, at least or up to 59°C, at least or up to 60°C, at least or up to 61 °C, at least or up to62°C, at least or up to 63°C, at least or up to 64°C, at least or up to 65°C, at least or up to66°C, at least or up to 67°C, at least or up to 68°C, at least or up to 69°C, at least or up to70°C, at least or up to 71°C, at least or up to 72°C, at least or up to 73°C, at least or up to74°C, at least or up to 75°C, at least or up to 76°C, at least or up to 77°C, at least or up to78°C, at least or up to 79°C, at least or up to 80°C, at least or up to 81 °C, at least or up toAttorney Ref: 42800-64265 / WO (001WO)82°C, at least or up to 83°C, at least or up to 84°C, at least or up to 85°C, at least or up to 86°C, at least or up to 87°C, at least or up to 88°C, at least or up to 89°C, at least or up to 90°C, at least or up to 91 °C, at least or up to 92°C, at least or up to 93°C, at least or up to 94 °C, at least or up to 95°C, at least or up to 96°C, at least or up to 97°C, at least or up to 98°C, at least or up to 99°C, or at least or up to 100°C. In some embodiments, the one or more pairs of primers are contacted with the one or more target polynucleotides at one or more temperatures of 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21 °C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61 °C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71 °C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81 °C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C.

[0200] In some embodiments, the amplifying increases the amount of the one or more target polynucleotides by between 0-fold to 100,000 fold. In some embodiments, the amplifying increases the amount of the one or more target polynucleotides by at least or up to 0 fold, at least or up to 5 fold, at least or up to 10 fold, at least or up to 20 fold, at least or up to 50 fold, at least or up to 100 fold, at least or up to 500 fold, at least or up to 1 ,000 fold, at least or up to 5,000 fold, at least or up to 10,000 fold, at least or up to 50,000 fold, or at least or up to 100,000 fold.

[0201] In some embodiments, each primer of the one or more pairs of primers is configured to bind to a target sequence specific to the one or more genes. In some embodiments, each primer of the one or more pairs of primers hybridizes to the target sequence specific to the one or more genes. In some embodiments, each primer of the one or more pairs of primers is specific to a target sequence present in one gene of the one or more genes. In some embodiments, the target sequence comprise an exon sequence. In some embodiments, the sequence comprise an intron sequence. In some embodiments, the target sequence comprise a conserved region of the one or more genes. A conserved region of the one or more genes can refer to a region of the one or more genes where the sequence of the region has remains unchanged or similar in sequence throughout evolution. In some embodiments, the conserved region of the one or more genes is identified from a reference genome.Attorney Ref: 42800-64265 / WO (001WO)

[0202] In some embodiments, the one or more pairs of primers comprise nucleic acid. In some embodiments, the nucleic acid is selected from the group consisting of: RNA, DNA 1,5-Anhydrohexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), fluoroarabino nucleic acid (FANA), and any combination thereof. In some embodiments, the one or more pairs of primers comprise RNA. In some embodiments, the one or more primers comprise DNA. In some embodiments, the one or more pairs of primers comprise single-stranded primers. In some embodiments, the one or more pairs of primers comprise double- stranded primers.

[0203] In some embodiments, each primer of the one or more pairs of primers comprises between 1 nucleotide to 50,000 nucleotides. In some embodiments, each primer of the one or more pairs of primers comprise at least or up to 1 nucleotide, at least or up to 2 nucleotides, at least or up to 3 nucleotides, at least or up to 4 nucleotides, at least or up to 5 nucleotides, at least or up to 6 nucleotides, at least or up to 7 nucleotides, at least or up to 8 nucleotides, at least or up to 9 nucleotides, at least or up to 10 nucleotides, at least or up to 11 nucleotides, at least or up to 12 nucleotides, at least or up to 13 nucleotides, at least or up to 14 nucleotides, at least or up to 15 nucleotides, at least or up to 16 nucleotides, at least or up to 17 nucleotides, at least or up to 18 nucleotides, at least or up to 19 nucleotides, at least or up to 20 nucleotides, at least or up to 21 nucleotides, at least or up to 22 nucleotides, at least or up to 23 nucleotides, at least or up to 24 nucleotides, at least or up to 25 nucleotides, at least or up to 26 nucleotides, at least or up to 27 nucleotides, at least or up to 28 nucleotides, at least or up to 29 nucleotides, at least or up to 30 nucleotides, at least or up to31 nucleotides, at least or up to 32 nucleotides, at least or up to 33 nucleotides, at least or up to 34 nucleotides, at least or up to 35 nucleotides, at least or up to 36 nucleotides, at least or up to 37 nucleotides, at least or up to 38 nucleotides, at least or up to 39 nucleotides, at least or up to 40 nucleotides, at least or up to 41 nucleotides, at least or up to 42 nucleotides, at least or up to 43 nucleotides, at least or up to 44 nucleotides, at least or up to 45 nucleotides, at least or up to 46 nucleotides, at least or up to 47 nucleotides, at least or up to 48 nucleotides, at least or up to 49 nucleotides, at least or up to 50 nucleotides, at least or up to 51 nucleotides, at least or up to 52 nucleotides, at least or up to 53 nucleotides, at least or up to 54 nucleotides, at least or up to 55 nucleotides, at least or up to 56 nucleotides, at least or up to 57 nucleotides, at least or up to 58 nucleotides, at least or up to 59 nucleotides, at least or up to 60 nucleotides, at least or up to 61 nucleotides, at least or up to 62Attorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 63 nucleotides, at least or up to 64 nucleotides, at least or up to 65 nucleotides, at least or up to 66 nucleotides, at least or up to 67 nucleotides, at least or up to 68 nucleotides, at least or up to 69 nucleotides, at least or up to 70 nucleotides, at least or up to 71 nucleotides, at least or up to 72 nucleotides, at least or up to 73 nucleotides, at least or up to 74 nucleotides, at least or up to 75 nucleotides, at least or up to 76 nucleotides, at least or up to 77 nucleotides, at least or up to 78 nucleotides, at least or up to 79 nucleotides, at least or up to 80 nucleotides, at least or up to 81 nucleotides, at least or up to 82 nucleotides, at least or up to 83 nucleotides, at least or up to 84 nucleotides, at least or up to 85 nucleotides, at least or up to 86 nucleotides, at least or up to 87 nucleotides, at least or up to 88 nucleotides, at least or up to 89 nucleotides, at least or up to 90 nucleotides, at least or up to 91 nucleotides, at least or up to 92 nucleotides, at least or up to 93 nucleotides, at least or up to 94 nucleotides, at least or up to 95 nucleotides, at least or up to 96 nucleotides, at least or up to 97 nucleotides, at least or up to 98 nucleotides, at least or up to 99 nucleotides, at least or up to 100 nucleotides, at least or up to 101 nucleotides, at least or up to 102 nucleotides, at least or up to 103 nucleotides, at least or up to 104 nucleotides, at least or up to 105 nucleotides, at least or up to 106 nucleotides, at least or up to 107 nucleotides, at least or up to 108 nucleotides, at least or up to 109 nucleotides, at least or up to 110 nucleotides, at least or up to 111 nucleotides, at least or up to 112 nucleotides, at least or up to 113 nucleotides, at least or up to 114 nucleotides, at least or up to 115 nucleotides, at least or up to 116 nucleotides, at least or up to 117 nucleotides, at least or up to 118 nucleotides, at least or up to 1 19 nucleotides, at least or up to 120 nucleotides, at least or up to 121 nucleotides, at least or up to 122 nucleotides, at least or up to 123 nucleotides, at least or up to 124 nucleotides, at least or up to 125 nucleotides, at least or up to 126 nucleotides, at least or up to 127 nucleotides, at least or up to 128 nucleotides, at least or up to 129 nucleotides, at least or up to 130 nucleotides, at least or up to 131 nucleotides, at least or up to 132 nucleotides, at least or up to 133 nucleotides, at least or up to 134 nucleotides, at least or up to 135 nucleotides, at least or up to 136 nucleotides, at least or up to 137 nucleotides, at least or up to 138 nucleotides, at least or up to 139 nucleotides, at least or up to 140 nucleotides, at least or up to 141 nucleotides, at least or up to 142 nucleotides, at least or up to 143 nucleotides, at least or up to 144 nucleotides, at least or up to 145 nucleotides, at least or up to 146 nucleotides, at least or up to 147 nucleotides, at least or up to 148 nucleotides, at least or up to 149 nucleotides, at least or up to 150 nucleotides, at least or up to 200 nucleotides, at least or up to 250 nucleotides, at least or up to 300 nucleotides, at least or up to 350 nucleotides, at least or up to 400Attorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 450 nucleotides, at least or up to 500 nucleotides, at least or up to 550 nucleotides, at least or up to 600 nucleotides, at least or up to 650 nucleotides, at least or up to 700 nucleotides, at least or up to 750 nucleotides, at least or up to 800 nucleotides, at least or up to 850 nucleotides, at least or up to 900 nucleotides, at least or up to 950 nucleotides, at least or up to 1 ,000 nucleotides, at least or up to 1 ,500 nucleotides, at least or up to 2,000 nucleotides, at least or up to 2,500 nucleotides, at least or up to 3,000 nucleotides, at least or up to 3,500 nucleotides, at least or up to 4,000 nucleotides, at least or up to 4,500 nucleotides, or at least or up to 5,000 nucleotides. In some embodiments, each primer of the one or more pairs of primers comprise 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, 30 nucleotides, 31 nucleotides, 32 nucleotides, 33 nucleotides, 34 nucleotides, 35 nucleotides, 36 nucleotides, 37 nucleotides, 38 nucleotides, 39 nucleotides, 40 nucleotides, 41 nucleotides, 42 nucleotides, 43 nucleotides, 44 nucleotides, 45 nucleotides, 46 nucleotides, 47 nucleotides, 48 nucleotides, 49 nucleotides, 50 nucleotides, 51 nucleotides, 52 nucleotides, 53 nucleotides, 54 nucleotides, 55 nucleotides, 56 nucleotides, 57 nucleotides, 58 nucleotides, 59 nucleotides, 60 nucleotides, 61 nucleotides, 62 nucleotides, 63 nucleotides, 64 nucleotides, 65 nucleotides, 66 nucleotides, 67 nucleotides, 68 nucleotides, 69 nucleotides, 70 nucleotides, 71 nucleotides, 72 nucleotides, 73 nucleotides, 74 nucleotides, 75 nucleotides, 76 nucleotides, 77 nucleotides, 78 nucleotides, 79 nucleotides, 80 nucleotides,81 nucleotides, 82 nucleotides, 83 nucleotides, 84 nucleotides, 85 nucleotides, 86 nucleotides, 87 nucleotides, 88 nucleotides, 89 nucleotides, 90 nucleotides, 91 nucleotides,92 nucleotides, 93 nucleotides, 94 nucleotides, 95 nucleotides, 96 nucleotides, 97 nucleotides, 98 nucleotides, 99 nucleotides, 100 nucleotides, 101 nucleotides, 102 nucleotides, 103 nucleotides, 104 nucleotides, 105 nucleotides, 106 nucleotides, 107 nucleotides, 108 nucleotides, 109 nucleotides, 110 nucleotides, 111 nucleotides, 112 nucleotides, 113 nucleotides, 114 nucleotides, 115 nucleotides, 116 nucleotides, 117 nucleotides, 118 nucleotides, 119 nucleotides, 120 nucleotides, 121 nucleotides, 122 nucleotides, 123 nucleotides, 124 nucleotides, 125 nucleotides, 126 nucleotides, 127 nucleotides, 128 nucleotides, 129 nucleotides, 130 nucleotides, 131 nucleotides, 132 nucleotides, 133 nucleotides, 134 nucleotides, 135 nucleotides, 136 nucleotides, 137Attorney Ref: 42800-64265 / WO (001WO) nucleotides, 138 nucleotides, 139 nucleotides, 140 nucleotides, 141 nucleotides, 142 nucleotides, 143 nucleotides, 144 nucleotides, 145 nucleotides, 146 nucleotides, 147 nucleotides, 148 nucleotides, 149 nucleotides, 150 nucleotides, 200 nucleotides, 250 nucleotides, 300 nucleotides, 350 nucleotides, 400 nucleotides, 450 nucleotides, 500 nucleotides, 550 nucleotides, 600 nucleotides, 650 nucleotides, 700 nucleotides, 750 nucleotides, 800 nucleotides, 850 nucleotides, 900 nucleotides, 950 nucleotides, 1,000 nucleotides, 1,500 nucleotides, 2,000 nucleotides, 2,500 nucleotides, 3,000 nucleotides,3,500 nucleotides, 4,000 nucleotides, 4,500 nucleotides, or 5,000 nucleotides. In some embodiments, each primer of the one or more pairs of primers comprises at least 15 nucleotides. In some embodiments, each primer of the one or more pairs of primers comprises 15 nucleotides to 40 nucleotides. In some embodiments, each primer of the one or more pairs of primers comprises 15 nucleotides to 30 nucleotides.

[0204] In some embodiments, each pair of the one or more pairs of primers are configured to amplify a sequence between 1 base pairs (bp) to 10,000 bp. In some embodiments, each pair of the one or more pairs of primers are configured to amplify a sequence of at least or up to 0 bp, at least or up to 10 bp, at least or up to 20 bp, at least or up to 30 bp, at least or up to 40 bp, at least or up to 50 bp, at least or up to 60 bp, at least or up to 70 bp, at least or up to 80 bp, at least or up to 90 bp, at least or up to 100 bp, at least or up to 200 bp, at least or up to 300 bp, at least or up to 400 bp, at least or up to 500 bp, at least or up to 600 bp, at least or up to 700 bp, at least or up to 800 bp, at least or up to 900 bp, at least or up to 1 ,000 bp, at least or up to 2,000 bp, at least or up to 3,000 bp, at least or up to 4,000 bp, at least or up to 5,000 bp, at least or up to 6,000 bp, at least or up to 7,000 bp, at least or up to 8,000 bp, at least or up to 9,000 bp, or at least or up to 10,000 bp. In some embodiments, each pair of the one or more pairs are configured to sequence in one or more genes selected from: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, mammalian orthologs, or any combination thereof. In some embodiments, each pair of the one or more pairs are configured to sequence in one or more genes selected from: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSC AFG00000001448, ABCC5, FOXL2, PIK3CD,Attorney Ref: 42800-64265 / WO (001WO)FBXW7, and mammalian orthologs. In some embodiments, the amplified sequence of the amplified target polynucleotides comprises one or more sequences corresponding to one or more exons of the one or more genes. In some embodiments, the amplified sequence of the amplified target polynucleotides comprises one or more sequences corresponding to one or more exons of the one or more genes selected from KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1 , SLC7A5, GNA 13, ENSC AFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, mammalian orthologs, or any combination thereof. In some embodiments, the amplified sequence of the amplified target polynucleotides comprises one or more sequences corresponding to one or more exons of the one or more genes selected from KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, F0XL2. PIK3CD, FBXW7, and mammalian orthologs.

[0205] In some embodiments, the one or more pairs of primers comprise one or more modified nucleotides. Modified nucleotides (e.g., natural nucleotides) refer to any nucleotide that is not adenine (A), guanine (G), thymine (T), cytosine (C), or uracil (U). In some embodiments, the one or more primers comprise natural nucleotides.

[0206] In some embodiments, the one or more modified nucleotides are selected from the group consisting of: 2-amino-deoxy adenosine, 2’-dInosine, 2’-dUridine, 2-thio-dT, 4-thio-dT, 4-thio-uridine, 5-Br-dC, 5-Br-dU, 5-Br-U, t-ethynyl-dU, 5-F-dU, 5-formyl-dC, 5- hydroxymethyl-dC, 5-hydroxymethyl-dU, 5-I-dC, 5-I-dU, 5-Iod-C, 5-Iod-U, 5-Me-C, 5- methyl-deoxy cytidine, 5-trifluormethyl-dU, 8-oxo-dG, aminoethyl-phenoxazine- deoxycytidine, C-5 propynyl-deoxycytidine, C-5 propynyl deoxyuridine, C8-alkyne-dC, C8- alkyene-dU, dimethyl-2’ -deoxy adenosine, formylindole, inosine, inverted end, iso-dC, iso- dG, Nl-methyl-pseudouridine, N4-ethyl-dC, N6,N6-dimethyl-rA, N6-Me-A, N6-Me-dA, N- POM caged-dT, perylene-dU, pseudouridine, and any combination thereof. In some embodiments, the one or more pairs of primers comprise between 0 modified nucleotides to 50 modified nucleotides. In some embodiments, the one or more pairs of primers comprise at least or up to 0 modified nucleotides, at least or up to 1 modified nucleotide, at least or up to 2 modified nucleotides, at least or up to 3 modified nucleotides, at least or up to 4 modifiedAttorney Ref: 42800-64265 / WO (001WO) nucleotides, at least or up to 5 modified nucleotides, at least or up to 6 modified nucleotides, at least or up to 7 modified nucleotides, at least or up to 8 modified nucleotides, at least or up to 9 modified nucleotides, at least or up to 10 modified nucleotides, at least or up to 11 modified nucleotides, at least or up to 12 modified nucleotides, at least or up to 13 modified nucleotides, at least or up to 14 modified nucleotides, at least or up to 15 modified nucleotides, at least or up to 16 modified nucleotides, at least or up to 17 modified nucleotides, at least or up to 18 modified nucleotides, at least or up to 19 modified nucleotides, at least or up to 20 modified nucleotides, at least or up to 21 modified nucleotides, at least or up to 22 modified nucleotides, at least or up to 23 modified nucleotides, at least or up to 24 modified nucleotides, at least or up to 25 modified nucleotides, at least or up to 26 modified nucleotides, at least or up to 27 modified nucleotides, at least or up to 28 modified nucleotides, at least or up to 29 modified nucleotides, at least or up to 30 modified nucleotides, at least or up to 31 modified nucleotides, at least or up to 32 modified nucleotides, at least or up to 33 modified nucleotides, at least or up to 34 modified nucleotides, at least or up to 35 modified nucleotides, at least or up to 36 modified nucleotides, at least or up to 37 modified nucleotides, at least or up to 38 modified nucleotides, at least or up to 39 modified nucleotides, at least or up to 40 modified nucleotides, at least or up to 41 modified nucleotides, at least or up to 42 modified nucleotides, at least or up to 43 modified nucleotides, at least or up to 44 modified nucleotides, at least or up to 45 modified nucleotides, at least or up to 46 modified nucleotides, at least or up to 47 modified nucleotides, at least or up to 48 modified nucleotides, at least or up to 49 modified nucleotides, or at least or up to 50 modified nucleotides. In some embodiments, the one or more pairs of primers comprise 0 modified nucleotides, 1 modified nucleotides, 2 modified nucleotides, 3 modified nucleotides, 4 modified nucleotides, 5 modified nucleotides, 6 modified nucleotides, 7 modified nucleotides, 8 modified nucleotides, 9 modified nucleotides, 10 modified nucleotides, 11 modified nucleotides, 12 modified nucleotides, 13 modified nucleotides, 14 modified nucleotides, 15 modified nucleotides, 16 modified nucleotides, 17 modified nucleotides, 18 modified nucleotides, 19 modified nucleotides, 20 modified nucleotides, 21 modified nucleotides, 22 modified nucleotides, 23 modified nucleotides, 24 modified nucleotides, 25 modified nucleotides, 26 modified nucleotides, 27 modified nucleotides, 28 modified nucleotides, 29 modified nucleotides, 30 modified nucleotides, 31 modified nucleotides, 32 modified nucleotides, 33 modified nucleotides, 34 modified nucleotides, 35 modified nucleotides, 36 modified nucleotides, 37 modifiedAttorney Ref: 42800-64265 / WO (001WO) nucleotides, 38 modified nucleotides, 39 modified nucleotides, 40 modified nucleotides, 41 modified nucleotides, 42 modified nucleotides, 43 modified nucleotides, 44 modified nucleotides, 45 modified nucleotides, 46 modified nucleotides, 47 modified nucleotides, 48 modified nucleotides, 49 modified nucleotides, or 50 modified nucleotides.

[0207] Alternatively, in some embodiments, the one or more pairs of primers may not comprise one or more modified nucleotides.

[0208] In some embodiments, the one or more pairs of primers comprise between one pair of primers to 600 pairs of primers. In some embodiments, the one or more pairs of primers comprise at least or up to one pair of primers, at least or up to 10 pairs of primers, at least or up to 20 pairs of primers, at least or up to 30 pairs of primers, at least or up to 40 pairs of primers, at least or up to 50 pairs of primers, at least or up to 60 pairs of primers, at least or up to 70 pairs of primers, at least or up to 80 pairs of primers, at least or up to 90 pairs of primers, at least or up to 100 pairs of primers, at least or up to 150 pairs of primers, at least or up to 200 pairs of primers, at least or up to 250 pairs of primers, at least or up to 300 pairs of primers, at least or up to 350 pairs of primers, at least or up to 400 pairs of primers, at least or up to 450 pairs of primers, at least or up to 500 pairs of primers, at least or up to 550 pairs of primers, or at least or up toa bout 600 pairs of primers.

[0209] In some embodiments, the one or more pairs of primers further comprise a detectable moiety. Non-limiting examples of detectable moieties include: 6-FAM, SUN™, IOE™, HEX™, MAX™, ATTO™ 425, Cy®3, ATTO™ 550, ROX™, Texas Red®-X, ATTO™ 590, ATTO™ 647N, ATTO™ 700, Cy®5, Cy®5.5, NHS-Fluorescein, FITC, Alexa 350, Pacific Blue®, Marina Blue™, Acridine Orange, Edans, Coumarin, BODIPY 493 / 503, Cy®2, BODIPY FL-X, DANSYL, Alexa 488, FAM, Oregon Green™, Rhodamine Green™-X, NBD-X, TET™, Alexa 430, BODIPY R6G-X, Yakima Yellow®, Alexa 532, VIC, R6G, Alexa 555, BODIPY 564 / 570, BODIPY TMR-X, Alexa 546, TAMRA, Rhodamine Red™- X, BODIPY 581 / 591, Redmond Red™, Cy®3.5, Alexa 568, Cal Red™, BODIPY TR-X, Alexa 594, BODIPY 630 / 650-X, LC Red 640, Alexa 633, BODIPY 650 / 665-X, Alexa 647, Alexa 660, Alexa 680, Alexa 700, Alexa 750, or any combination thereof.

[0210] In some embodiments, the one or more pairs of primers further comprise a quencher moiety. Non-limiting examples of quencher moieties include ZEN™, TAO™, Iowa Black™ FQ, Iowa Black™ RQ, Black Hole Quencher (BHQ)®-3, BHQ®-0, QSY-35, Eclipse®,Attorney Ref: 42800-64265 / WO (OOIWO)DABCYL, BHQ®-1, QSY™-7, QSY™-9, BHQ®-2, QSY™-21, Blackberry Quencher® (BBQ650®), TAMRA, or any combination thereof.

[0211] In some embodiments, the one or more pairs of primers further comprise a detectable moiety and a quencher moiety. In some embodiments, the detectable moiety and the quencher moiety are coupled to each primer of the one or more pairs of primers. In some embodiments, the detectable moiety and the quencher moiety are coupled one primer of the one or more pairs of primers. In some embodiments, the detectable moiety may not be detected when both the detectably moiety and the quencher moiety are coupled to the one or more pairs of primers. In some embodiments, the detectable moiety is detected when the detectable moiety is released from the one or more pairs of primers. In some embodiments, the detectable moiety is detected when the quencher moiety is released from the one or more pairs of primers.

[0212] In some embodiments, the step of generating the sequence information further comprises coupling one or more sequencing adaptors to (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to the one or more target polynucleotides hybridized with the one or more probes. In some embodiments, the one or more sequencing adaptors are coupled to the enriched target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to the enriched and amplified target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to the amplified target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides via ligation. In some embodiments, the one or more sequencing adaptors are coupled to (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides via hybridization. In some embodiments, the one or more sequencing adaptors are coupled to the 5’ end of (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplifiedAttorney Ref: 42800-64265 / WO (OOIWO) target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to the 3’ end of (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides. In some embodiments, the one or more sequencing adaptors are coupled to the 5’ end and the 3’ end of (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides.

[0213] In some embodiments, the step of generating the sequence information further comprises sequencing (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, (iii) enriched and amplified target polynucleotides, or (iv) the amplified target polynucleotides. In some embodiments, the one or more target polynucleotides hybridized with the one or more probes are sequenced. In some embodiments, the enriched target polynucleotides are sequenced. In some embodiments, the enriched and amplified target polynucleotides are sequenced. In some embodiments, the amplified target polynucleotides are sequenced. In some embodiments, the sequencing is performed by next generation sequencing. In some embodiments, the next generation sequencing is short-read sequencing. In some embodiments, the next generation sequencing is long-read sequencing. In some embodiments, the next generation sequencing comprises sequencing by synthesis. In some embodiments, the next generation sequencing comprises sequencing by ligation. In some embodiments, the next generation sequencing comprises sequencing by hybridization. In some embodiments, the next generation sequencing comprises 454 pyrosequencing.

[0214] In some embodiments, the step of sequencing further comprises identifying one or more mutations in the one or more genes. In some embodiments, the step of sequencing generates a plurality of sequenced polynucleotides. In some embodiments, the step of generating the sequence information further comprises aligning the sequenced polynucleotides with a reference genome. In some embodiments, the aligning the sequenced polynucleotides with the reference genome identifies the one or more mutations in the one or more genes. In some embodiments, the reference genome is a genome of a mammal. In some embodiments, the mammal is selected from the group consisting of: human, feline, canine, cattle, pig, sheep, horse, goat, donkey, rabbit, ferret, llama, buffalo, any and combinationAttorney Ref: 42800-64265 / WO (001WO) thereof. In some embodiments, the reference genome is the genome of a human. In some embodiments, the reference genome is the genome of a canine. In some embodiments, the reference genome is the genome of a feline. In some embodiments, the reference genome is a genome of a bird. In some embodiments, the bird is selected from the group consisting of: duck, parrot, parakeet, lovebird, finch, macaw, goose, and any combination thereof.

[0215] In some embodiments, the step of generating the sequence information further comprises performing quantitative PCR (qPCR). In some embodiments, the qPCR is configured to detect the one or more mutations in real-time. In some embodiments, the one or more pairs of primers are completely complementary (e.g., 100% complementary) to the one or more mutations in the one or more genes. In some embodiments, the one or more primers are completely complementary to the one or more mutations in the one or more genes selected from KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2. PIK3CD, FBXW7, and mammalian orthologs.

[0216] In some embodiments, the sequence information generated by qPCR is the total number of copies of sequences with the one or more mutations in the one or more genes. In some embodiments, the sequence information generated by qPCR is in the form of a quantification cycle (Cq) value. In some embodiments, the sequence information generated by the qPCR determines the presence of the one or more mutations in the one or more genes. In some embodiments, if the Cq value of the subject’s DNA sample is higher than the Cq value of a threshold control, then the one or more mutations are present in the one or more genes. In some embodiments, if the Cq value of the subject’s DNA sample is equal to the Cq value of a threshold control, then the one or more mutations are present in the one or more genes. In some embodiments, the sequence information generated by the qPCR determines the absence of the one or more mutations in the one or more genes. In some embodiments, if the Cq value of the subject’s DNA is lower than the Cq value of a threshold control, then the one or more mutations are absent in the one or genes.

[0217] In some embodiments, the threshold control is a gene that is expressed at normal levels in a subject. In some embodiments, the expression level of the one or more genes is compared to the expression level of the threshold control gene. In some embodiments, theAttorney Ref: 42800-64265 / WO (001WO) threshold control gene is selected from glyceraldehyde- 3 -phospate dehydrogenase (GAPDH), P-actin (ACTB), hypoxanthine phosphoribosyl transferase (HPRT1), 2M (B2M), ubiquitin C (UBC), 18S rRNA (RNA18S1), 28S rRNA (RNA28S1), a-tubulin (TUBA), albumin (ALB), ribosomal protein L32 (RPL32), TATA sequence binding protein (TBP), cyclophilin C (CYCC), elongation factor la (EF1A), and RNA polymerase II (RPII).

[0218] In some embodiments, the performing qPCR further comprises including a wild- type control sample. In some embodiments, the wild-type control sample is a DNA sample where the one or more mutations in the one or more genes are absent. In some embodiments, if the Cq value of the subject’s DNA sample is similar to the Cq value of the wild-type control, then the one or more mutations in the one or more genes are absent in the subject.

[0219] In some embodiments, the performing qPCR further comprises including a heterozygous control sample. In some embodiments, the heterozygous control sample is a DNA sample where the one or more mutations in the one or more genes are present in one chromosome of the DNA sample. In some embodiments, if the Cq value of the subject’s DNA sample is similar to the Cq value of the heterozygous control, then the one or more mutations in the one or more genes are present in one chromosome of the subject.

[0220] In some embodiments, the performing qPCR further comprises including a homozygous control sample. In some embodiments, the homozygous control sample is a DNA sample where the one or more mutations in the one or more genes are present in both chromosomes of the DNA sample. In some embodiments, if the Cq value of the subject’s DNA sample is similar to the Cq value of the homozygous control, then the one or more mutations in the one or more genes are present in both chromosomes of the subject.

[0221] In some embodiments, the performing qPCR further comprises including a wild- type discrimination probe. In some embodiments, the wild-type discrimination probe is a mismatch-discriminating probe. In some embodiments, the mismatch-discriminating probe amplifies the one or more genes if the one or more mutations are present. In some embodiments, the mismatch-discriminating probe does not amplify the one or more genes if the one or more mutations are absent. In some embodiments, the wild-type discrimination probe is a blocking probe. In some embodiments, the blocking probe does not amplify the one or more genes if the one or more mutations are absent.Attorney Ref: 42800-64265 / WO (OOIWO)

[0222] In some embodiments, the one or more pairs of primers further comprise a detectable moiety and a quencher moiety. In some embodiments, the one or more pairs of primers are coupled to a detectable moiety. In some embodiments, the one or more pairs of primers are coupled to a quencher moiety. In some embodiments, each primer of the one or more pairs of primers are coupled to a detectable moiety and a quencher moiety. In some embodiments, one primer of the one or more pairs of primers are coupled to a detectable moiety and a quencher moiety. In some embodiments, the detectable moiety and / or the quencher moiety are coupled to the one or more pairs of primers via a covalent bond. In some embodiments, the covalent bond is a polar covalent bond or a non-polar covalent bond. In some embodiments, the detectable moiety and / or the quencher moiety are coupled to the one or more pairs of primers via a non-covalent bond. Non-limiting examples of non-covalent bonds include hydrogen bonds, hydrophobic interactions, halogen bonding, van der Waals forces, London dispersion interactions, electrostatic interactions, ionic bonds, or any combination thereof.

[0223] In some embodiments, the one or more pairs of primers hybridize with the one or more target polynucleotides if the one or more mutations in the one or more genes are present. In some embodiments, the one or more pairs of primers hybridize with the one or more mutations in the one or more genes. In some embodiments, the one or more pairs of primers are coupled to the detectable moiety and the quencher moiety when hybridized with the one or more mutations in the one or more genes. In some embodiments, the one or more pairs of primers coupled to the detectable moiety and the quencher moiety may not be detected when hybridized with the one or more mutations in the one or more genes. In some embodiments, once the one or more pairs of primers are hybridized to the one or more mutations in the one or more genes, the one or more pairs of primers are extended by one or more polymerases using the one or more target polynucleotides as a template. In some embodiments, during the extension of the one or more pairs of primers, the detectable moiety is removed (e.g., released) from the one or more pairs of primers by the one or more polymerases. In some embodiments, when the detectable moiety is released from the one or more pairs of primers, the detectable moiety is detected. In some embodiments, during the extension of the one or more pairs of primers, the quencher moiety is removed from the one or more pairs of primers by the one or more polymerases. In some embodiments, when the quencher moiety is removed from the one or more pairs of primers, the detectable moiety is detected. In some embodiments, detection of the detectable moiety indicates a presence of the one or more mutations in the one or more genes.Attorney Ref: 42800-64265 / WO (OOIWO)

[0224] In some embodiments, the one or more pairs of primers may not hybridize to the one or more genes if the one or more mutations are absent from the one or more genes. In some embodiments, lack of detection of the detectable moieties indicates an absence of the one or more mutations in the one or more genes.

[0225] In some embodiments, the one or more mutations are selected from the group consisting of: point mutations, frameshift mutation, chromosomal mutations, indel mutations, copy number variations, and any combination thereof. In some embodiments, the one or more mutations results in no change of function of the one or more genes. In some embodiments, the one or more mutations results in a modified function of the one or more genes. In some embodiments, the one or more mutations results in a loss of function of the one or more genes. In some embodiments, the one or more mutations results in an enhanced function of the one or more genes. In some embodiments, the one or more mutations results in a loss of one or more stop codons in the one or more genes. In some embodiments, the one or more mutations results in a gain of one or more stop codons in the one or more genes. In some embodiments, the one or more mutations results in a loss of one or more start codons in the one or more genes.

[0226] In some embodiments, the one or more mutations are point mutations. In some embodiments, the point mutations comprise substitution of a nucleotide, deletion of a nucleotide, insertion of a nucleotide, or any combination thereof. In some embodiments, the point mutations comprise one or more single nucleotide variants (SNVs). In some embodiments, the point mutations comprise a silent mutation (e.g., mutated codon codes for the same amino acid). In some embodiments, the point mutations comprise a missense mutation (e.g., mutated codon codes for a different amino acid). In some embodiments, the point mutations comprise a nonsense mutation (e.g., mutated codon is a premature stop codon). In some embodiments, the point mutations comprise missense mutations, silent mutations, nonsense mutations, or any combination thereof.

[0227] In some embodiments, the one or more mutations are frameshift mutations. Frameshift mutations can comprise inserting or deleting one or more nucleotides which results in an altered reading frame. In some embodiments, the one or more mutations are indel (insertion-deletion) mutations. Indel mutations can comprise insertion or deletion of one or more nucleotides in the subject’s genome.Attorney Ref: 42800-64265 / WO (001WO)

[0228] In some embodiments, the one or more mutations are chromosomal mutations. In some embodiments, the chromosomal mutations comprise inversion of one or more regions in a chromosome, deletion of one or more regions in a chromosome, duplication of one or more regions in a chromosome, insertion of one or more regions in a chromosome, nondisjunction of one or more chromosomes (e.g., failure of one or more chromosomes to separate during meiosis), one or more translocation mutations (e.g., one region from a first chromosome attached to a second chromosome), or any combination thereof.

[0229] In some embodiments, the one or more mutations are copy number variations. In some embodiments, the copy number variation mutations comprise gene amplification (e.g., number of copies of a gene is increased), expanding trinucleotide repeat (e.g., number of repeated trinucleotide sequences is increased), or any combination thereof.

[0230] In some embodiments, the one or more mutations are somatic mutations. Somatic mutations can refer to mutations that occur in any cell of the subject’s body except the germline cells. In some embodiments, the one or more mutations are germline mutations.Germline mutations can refer to mutations that occur in germline cells and are present in every cell of the subject. In some embodiments, the one or more mutations are somatic mutations and germline mutations. In some embodiments, somatic mutations comprise one or more mutations present in a diseased tissue sample. In some embodiments, germline mutations comprise one or more mutations present in a healthy tissue sample. In some embodiments, somatic mutations comprise one or more mutations present in a diseased tissue sample that are absent in a healthy tissue sample. In some embodiments, germline mutations comprise one or more mutations present in a healthy tissue sample and a diseased tissue sample.

[0231] In some embodiments, the one or more mutations comprise between one mutation to 1,000 mutations. In some embodiments, the one or more mutations comprise at least or up to one mutation, at least or up to two mutations, at least or up to three mutations, at least or up to four mutations, at least or up to five mutations, at least or up to six mutations, at least or up to seven mutations, at least or up to eight mutations, at least or up to nine mutations, at least or up to ten mutations, at least or up to 20 mutations, at least or up to 30 mutations, at least or up to 40 mutations, at least or up to 50 mutations, at least or up to 60 mutations, at least or up to 70 mutations, at least or up to 80 mutations, at least or up to 90 mutations, at least or up to 100 mutations, at least or up to 200 mutations, at least or up to 300 mutations, at least or up toAttorney Ref: 42800-64265 / WO (001WO)400 mutations, at least or up to 500 mutations, at least or up to 600 mutations, at least or up to 700 mutations, at least or up to 800 mutations, at least or up to 900 mutations, or at least or up to 1,000 mutations.

[0232] In some embodiments, the one or more mutations in the one or more genes are validated. In some embodiments, the one or more mutations in the one or more genes are validated by comparing the sequences of the one or more genes in the subject to additional sequences of the one or more genes from a healthy subject. In some embodiments, the healthy subject may not have cancer or has not been diagnosed with the cancer. In some embodiments, if the one or more mutations in the one or more genes in the subject are present in the additional sequences of the one or more genes from the healthy subject, then the one or more mutations are removed from the analysis. In some embodiments, if the one or more mutations in the one or more genes in the subject are present in the additional sequences of the one or more genes from the healthy subject, then the one or more mutations in the one or more genes in the subject may not be mutations. In some embodiments, if the one or more mutations in the one or more genes in the subject are absent in the additional sequences of the one or more genes from the healthy subject, then the one or more mutations are included in the analysis. In some embodiments, if the one or more mutations in the one or more genes in the subject are absent in the additional sequences of the one or more genes from the healthy subject, then the one or more mutations in the one or more genes in the subject are mutations.5.2.4. Types of Genes

[0233] In some embodiments, the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, MTOR, KLF4, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, any mammalian orthologs thereof, and any combination thereof. In some embodiments, the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1,Attorney Ref: 42800-64265 / WO (OOIWO)ATM, BRCA1, VEGFA, ABL1 any mammalian orthologs thereof, and any combination thereof. In some embodiments, the mammalian ortholog of the one or more genes is a human ortholog. In some embodiments, the mammalian ortho log of the one or more genes is a canine ortholog. In some embodiments, the mammalian ortholog of the one or more genes is a feline ortholog.

[0234] In some embodiments, the one or more genes comprises one or more sequences selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , fragments thereof, and any combination thereof.

[0235] In some embodiments, the one or more genes is lysine methyltransferase 2C (KMT2C) or a mammalian ortholog thereof. In some embodiments, the KMT2C gene comprises the sequence of SEQ ID NO: 1 (ENSCAFT00000007959) or a fragment thereof. In some embodiments, the one or more genes is lysine methyltransferase 2D (KMT2D) or a mammalian ortholog thereof. In some embodiments, the KMT2D gene comprises the sequence of SEQ ID NO: 2 (ENSCAFT00000081492) or a fragment thereof. In some embodiments, the one or more genes is BCL11 transcription factor B (BCL1 IB) or a mammalian ortholog thereof. In some embodiments, the BCL1 IB gene comprises the sequence of SEQ ID NO: 3 (ENSCAFT00000028248) or a fragment thereof. In some embodiments, the one or more genes is notch receptor 2 (NOTCH2) or a mammalian ortholog thereof. In some embodiments, the NOTCH2 gene comprises the sequence of SEQ ID NO: 4 (ENSC AFT00000016889) or a fragment thereof. In some embodiments, the one or more genes is TNF receptor associated factor 3 (TRAF3) or a mammalian ortholog thereof. In some embodiments, the TRAF3 gene comprises the sequence of SEQ ID NO: 5 (ENSCAFT00000028719) or a fragment thereof. In some embodiments, the one or more genes is cyclin DI (CCND1) or a mammalian ortholog thereof. In some embodiments, the CCND1 gene comprises the sequence of SEQ ID NO: 6 (ENSCAFT00000017023) or a fragment thereof. In some embodiments, the one or more genes is AT-rich interaction domain 1A (ARID1 A) or a mammalian ortholog thereof. In some embodiments, the ARID1 A gene comprises the sequence of SEQ ID NO: 7 (ENSCAFT00000019631) or a fragment thereof. In some embodiments, the one or more genes is CREB binding protein (CREBBP) or aAttorney Ref: 42800-64265 / WO (OOIWO) mammalian ortholog thereof. In some embodiments, the CREBBP gene comprises the sequence of SEQ ID NO: 8 (ENSCAFT00000044601) or a fragment thereof. In some embodiments, the one or more genes is tumor protein p53 (TP53) or a mammalian ortholog thereof. In some embodiments, the TP53 gene comprises the sequence of SEQ ID NO: 9 (ENSCAFT00000081814) or a fragment thereof. In some embodiments, the one or more genes is sperm flagellar 2 (SPEF2) or a mammalian ortholog thereof. In some embodiments, the SPEF2 gene comprises the sequence of SEQ ID NO: 10 (ENSCAFT00000044134) or a fragment thereof. In some embodiments, the one or more genes is cyclin D3 (CCND3) or a mammalian ortholog thereof. In some embodiments, the CCND3 gene comprises the sequence of SEQ ID NO: 11 (ENSCAFTOOOOOO813O3) or a fragment thereof. In some embodiments, the one or more genes is protection of telomeres 1 (POTI) or a mammalian ortholog thereof. In some embodiments, the POTI gene comprises the sequence of SEQ ID NO: 12 (ENSCAFT00000086242) or a fragment thereof. In some embodiments, the one or more genes is SET domain containing 2 (SETD2) or a mammalian ortholog thereof. In some embodiments, the SETD2 gene comprises the sequence of SEQ ID NO: 13 (ENSCAFT00000021260) or a fragment thereof. In some embodiments, the one or more genes is replication factor C subunit 1 (RFC1) or a mammalian ortholog thereof. In some embodiments, the RFC1 gene comprises the sequence of SEQ ID NO: 14 (ENSCAFT00000070204) or a fragment thereof. In some embodiments, the one or more genes is TNF receptor superfamily member 1 la (TNFRSF11A) or a mammalian ortholog thereof. In some embodiments, the TNFRSF11A gene comprises the sequence of SEQ ID NO: 15 (ENSCAFT00000000128) or a fragment thereof. In some embodiments, the one or more genes is ATP binding cassette subfamily C member 4 (ABCC4) or a mammalian ortholog thereof. In some embodiments, the ABCC4 gene comprises the sequence of SEQ ID NO: 16 (ENSCAFT00000070709) or a fragment thereof. In some embodiments, the one or more genes is melanocyte inducing transcription factor (MITF) or a mammalian ortholog thereof. In some embodiments, the one or more genes is cadherin 1 (CDH1) or a mammalian ortholog thereof. In some embodiments, the one or more genes is nuclear protein (NPAT) or a mammalian ortholog thereof. In some embodiments, the one or more genes is enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) or a mammalian ortholog thereof. In some embodiments, the one or more genes is MYC proto-oncogene (MYC) or a mammalian ortholog thereof. In some embodiments, the MYC gene comprises the sequence of SEQ ID NO: 19 (ENSCAFT00000001656) or a fragment thereof. In some embodiments, the one or more genes is TBL1X / Y related 1 (TBL1XR1) or a mammalian ortholog thereof. In someAttorney Ref: 42800-64265 / WO (OOIWO) embodiments, the one or more genes is F-box and WD repeat domain containing 7 (FBXW7) or a mammalian ortholog thereof. In some embodiments, the one or more genes is mechanistic target of rapamycin kinase (MTOR) or a mammalian ortholog thereof. In some embodiments, the one or more genes is SATB homeobox 1 (SATB1) or a mammalian ortholog thereof. In some embodiments, the one or more genes is forkhead box 01 (F0X01) or a mammalian ortholog thereof. In some embodiments, the one or more genes is dynein cytoplasmic 1 intermediate chain 2 (DYNC112) or a mammalian ortholog thereof. In some embodiments, the one or more genes is tumor protein p73 (TP73) or a mammalian ortholog thereof. In some embodiments, the one or more genes is phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit delta (PIK3CD) or a mammalian ortholog thereof. In some embodiments, the one or more genes is NLR family pyrin domain containing 5 (NLRP5) or a mammalian ortholog thereof. In some embodiments, the one or more genes is BCL10 immune signaling adaptor (BCL10) or a mammalian ortholog thereof. In some embodiments, the one or more genes is El A binding protein p300 (EP300) or a mammalian ortholog thereof. In some embodiments, the one or more genes is myocyte enhancer factor 2C (MEF2C) or a mammalian ortholog thereof. In some embodiments, the one or more genes is toll like receptor 9 (TLR9) or a mammalian ortholog thereof. In some embodiments, the one or more genes is ABL proto-oncogene 1 (ABL1) or a mammalian ortholog thereof. In some embodiments, the ABL1 gene comprises the sequence of SEQ ID NO: 17 (ENSCAFT00000031723) or a fragment thereof. In some embodiments, the one or more genes is KIT proto-oncogene (CKIT) or a mammalian ortholog thereof. In some embodiments, the one or more genes is B-Raf proto-oncogene (BRAF) or a mammalian ortholog thereof. In some embodiments, the one or more genes is tumor necrosis factor (TNF) or a mammalian ortholog thereof. In some embodiments, the one or more genes is BTG antiproliferation factor 1 (BTG1) or a mammalian ortholog thereof. In some embodiments, the one or more genes is ATM serine / threonine kinase (ATM) or a mammalian ortholog thereof. In some embodiments, the ATM gene comprises the sequence of SEQ ID NO: 18 (ENSCAFT00000048574) or a fragment thereof. In some embodiments, the one or more genes is BRCA1 DNA repair associated (BRCA1) or a mammalian ortholog thereof. In some embodiments, the BRCA1 gene comprises the sequence of SEQ ID NO: 21 (ENSCAFT00000071681) or a fragment thereof. In some embodiments, the one or more genes is vascular endothelial growth factor A (VEGFA) or a mammalian ortholog thereof. In some embodiments, the VEGFA gene comprises the sequence of SEQ ID NO: 20 (ENSCAFT00000049819) or a fragment thereof. In some embodiments, the one or moreAttorney Ref: 42800-64265 / WO (001WO) genes is mechanistic target of rapamycin kinase (MTOR). In some embodiments, the one or more genes is KLF transcription factor 4 (KLF4). In some embodiments, the one or more genes is IL2 inducible T cell kinase (ITK). In some embodiments, the one or more genes is solute carrier family 19 member 1 (SLC19A1). In some embodiments, the one or more genes is solute carrier family 7 member 5 (SLC7A5). In some embodiments, the one or more genes is G protein subunit alpha 13 (GNA13). In some embodiments, the one or more genes is Pim- 1 proto-oncogene (PIM1). In some embodiments, the PIM1 gene comprise the sequence of ENSCAFG00000001448 or a fragment thereof. In some embodiments, the one or more genes is ATP binding cassette subject C member 5 (ABCC5). In some embodiments, the one or more genes is forkhead box L2 (FOXL2).

[0236] In some embodiments, the one or more genes comprise any of the nucleic acid sequences listed in Table 1.

[0237] In some embodiments, the one or more genes have a sequence identity of between 0% to 100% to one or more sequences selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO:18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and any combination thereof. In some embodiments, the one or more genes have a sequence identity of at least or up to 0%, at least or up to 5%, at least or up to 10%, at least or up to 15%, at least or up to 20%, at least or up to 25%, at least or up to 30%, at least or up to 35%, at least or up to 40%, at least or up to45%, at least or up to 50%, at least or up to 55%, at least or up to 60%, at least or up to 65%, at least or up to 70%, at least or up to 75%, at least or up to 80%, at least or up to 85%, at least or up to 90%, at least or up to 95%, at least or up to 96%, at least or up to 97%, at least or up to 98%, at least or up to 99%, at least or up to 99.5%, at least or up to99.8%, at least or up to 99.9%, or at least or up to 100% to one or more sequences selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO:10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and any combination thereof.Attorney Ref: 42800-64265 / WO (001WO)

[0238] In some embodiments, the one or more target polynucleotides comprise a sequence of a target polynucleotide with a sequence identity of between 0% to 100% to one or more sequences selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19,SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof. In some embodiments, the one or more target polynucleotides comprise a sequence of a target polynucleotide with a sequence identity of at least or up to 0%, at least or up to 5%, at least or up to 10%, at least or up to15%, at least or up to 20%, at least or up to 25%, at least or up to 30%, at least or up to 35%, at least or up to 40%, at least or up to 45%, at least or up to 50%, at least or up to 55%, at least or up to 60%, at least or up to 65%, at least or up to 70%, at least or up to 75%, at least or up to 80%, at least or up to 85%, at least or up to 90%, at least or up to 95%, at least or up to 96%, at least or up to 97%, at least or up to 98%, at least or up to99%, at least or up to 99.5%, at least or up to 99.8%, at least or up to 99.9%, or at least or up to 100% to one or more sequences selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO:7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.

[0239] In some embodiments, the one or more genes is a single gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1 , DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are two different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, AR1D1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are three different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B,Attorney Ref: 42800-64265 / WO (OOIWO)N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof In some embodiments, the one or more genes are four different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1 , NPAT, EZH2, MYC, TBL1XR1 , FBXW7, MTOR, SATB 1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are five different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof. In some embodiments, the one or more genes are six different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABLE CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof. In some embodiments, the one or more genes are seven different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABLE CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are eight different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1,ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (OOIWO)

[0240] In some embodiments, the one or more genes are nine different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are ten different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID 1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 11 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 12 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 13 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 14 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABLE CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLEAttorney Ref: 42800-64265 / WO (OOIWO) and mammalian orthologs thereof. In some embodiments, the one or more genes are 15 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof.

[0241] In some embodiments, the one or more genes are 16 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1 , FBXW7, MTOR, SATB1, FOXO1 , DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 17 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 18 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABLE CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof. In some embodiments, the one or more genes are 19 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 20 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF,Attorney Ref: 42800-64265 / WO (OOIWO)CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 21 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCLIO, EP300, MEF2C, TLR9, ABL1 , CKIT, BRAF, TNF, BTG1, ATM, BRCA1 , VEGFA, ABL1 , and mammalian orthologs thereof.

[0242] In some embodiments, the one or more genes are 22 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1 , ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 23 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XRI, FBXW7, MTOR, SATBI, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCLIO, EP300, MEF2C, TLR9, ABL1 , CKIT, BRAF, TNF, BTG1, ATM, BRCA1 , VEGFA, ABL1 , and mammalian orthologs thereof. In some embodiments, the one or more genes are 24 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATBI, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 25 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATBI, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 26 different genes selected from the groupAttorney Ref: 42800-64265 / WO (OOIWO) consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 27 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1, TNFRSF11 A, ABCC4, MITF, CDH1 , NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof. In some embodiments, the one or more genes are 28 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof.

[0243] In some embodiments, the one or more genes are 29 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1, TNFRSF11 A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABLE and mammalian orthologs thereof. In some embodiments, the one or more genes are 30 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 31 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C,Attorney Ref: 42800-64265 / WO (OOIWO)TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 32 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 33 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 34 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 35 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof.

[0244] In some embodiments, the one or more genes are 36 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 37 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2,Attorney Ref: 42800-64265 / WO (OOIWO)CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 38 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1 , FOXO1 , DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 39 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, F0X01, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof.

[0245] In some embodiments, the one or more genes are 40 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1 , ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 41 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 42 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, and mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (OOIWO)

[0246] In some embodiments, the one or more genes are KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, MITF, CDH1, NPAT, EZH2, MYC, TBL1XR1, FBXW7, MTOR, SATB1, FOXO1, DYNC112, TP73, PIK3CD, NLRP5, BCL10, EP300, MEF2C, TLR9, ABL1, CKIT, BRAF, TNF, BTG1, ATM, BRCA1, VEGFA, ABL1, or mammalian orthologs thereof.

[0247] In some embodiments, the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, mammalian orthologs thereof, and any combination thereof.

[0248] In some embodiments, the one or more genes is a single gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are two different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are three different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are four different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are five different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are six different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1 , TNFRSF11 A, ABCC4, ATM, BRCA1 , MYC, VEGFA,Attorney Ref: 42800-64265 / WO (OOIWO)ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are seven different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are eight different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof.

[0249] In some embodiments, the one or more genes are nine different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1 , TNFRSF11 A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are ten different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 11 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 12 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 13 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 14 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 15 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2,Attorney Ref: 42800-64265 / WO (001WO)RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 16 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0250] In some embodiments, the one or more genes are 17 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1 , ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 18 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 I B, NOTCH2, TRAF3, CCND1 , ARID 1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 19 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes are 20 different genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof.

[0251] In some embodiments, the one or more genes are KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID 1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF11 A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof.

[0252] In some embodiments, the one or more genes the first 20 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1 , ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 19 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes theAttorney Ref: 42800-64265 / WO (OOIWO) first 18 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 17 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0253] In some embodiments, the one or more genes the first 16 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof. In some embodiments, the one or more genes the first 15 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 14 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 13 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1 , ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 12 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0254] In some embodiments, the one or more genes the first 11 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 10 genes selected from the group consisting of: KMT2C, KMT2D, BCL11 B, NOTCH2, TRAF3, CCND1 , ARID 1 A, CREBBP, TP53, SPEF2,Attorney Ref: 42800-64265 / WO (OOIWO)CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 9 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 8 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI , SETD2, RFC1 , TNFRSF11 A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0255] In some embodiments, the one or more genes the first 7 genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1 , ARID1 A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 6 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 5 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11 A, ABCC4, ATM, BRCA1 , MYC, VEGFA, ABL1 , and mammalian orthologs thereof. In some embodiments, the one or more genes the first 4 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

[0256] In some embodiments, the one or more genes the first 3 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof. In some embodiments, the one or more genes the first 2 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1 , and mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (001WO)

[0257] In some embodiments, the one or more genes are KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, and TP53, or mammalian orthologs thereof.

[0258] In some embodiments, the one or more genes are PIK3CD, NOTCH2, KMT2C, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof.

[0259] In some embodiments, the one or more genes are FBXW7, TRAF3, KMT2D, CCND1, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof.

[0260] In some embodiments, the one or more genes are TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and FBXW7, or mammalian orthologs thereof.

[0261] In some embodiments, the one or more genes are TRAF3, KMT2D, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and KMT2D, or mammalian orthologs thereof.

[0262] In some embodiments, the one or more genes are PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are PIK3CD and CREBBP, or mammalian orthologs thereof.

[0263] In some embodiments, the one or more genes are SETD2, TP53, TRAF3, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are SETD2, TP53, and TRAF3, or mammalian orthologs thereof.

[0264] In some embodiments, the one or more genes are KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are KMT2C and NOTCH2, or mammalian orthologs thereof. In some embodiments, the one or more genes are KMT2D, KMT2C, mammalian orthologs thereof, or any combinationAttorney Ref: 42800-64265 / WO (OOIWO) thereof. In some embodiments, the one or more genes are KMT2D and KMT2C, or mammalian orthologs thereof. In some embodiments, the one or more genes are KMT2C, BCL1 IB, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are KMT2C and BCL1 IB, or mammalian orthologs thereof. In some embodiments, the one or more genes are KMT2D, N0TCH2, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are KMT2D and N0TCH2, or mammalian orthologs thereof.

[0265] In some embodiments, the one or more genes are TRAF3, SETD2, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and SETD2, or mammalian orthologs thereof. In some embodiments, the one or more genes are TRAF3, POTI , mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and POTI, or mammalian orthologs thereof. In some embodiments, the one or more genes are TRAF3, TBL1XR1, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and TBL1XR1, or mammalian orthologs thereof. In some embodiments, the one or more genes are TP53, SETD2, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TP53 and SETD2, or mammalian orthologs thereof. In some embodiments, the one or more genes are POTI, FBXW7, mammalian orthologs thereof, of any combination thereof. In some embodiments, the one or more genes are POTI and FBXW7, or mammalian orthologs thereof.

[0266] In some embodiments, the one or more genes are MTOR, KLF4, VEGFA, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are MTOR, KLF4, and VEGFA, or mammalian orthologs thereof. In some embodiments, the one or more genes are MTOR, KLF4, ITK, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are MTOR, KLF4, and ITK, or mammalian orthologs thereof. In some embodiments, the one or more genes are CCND1, KMT2D, TP53, ARID1A, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are CCND1, KMT2D, TP53, and ARID 1 A, or mammalian orthologs thereof. In some embodiments, the one or more genes are CCND1, TP53, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are CCND1 and TP53, or mammalian orthologs thereof. In some embodiments, the one or more genes are TP53, SETD2, SLC7A5, mammalian orthologsAttorney Ref: 42800-64265 / WO (001WO) thereof, or any combination thereof. In some embodiments, the one or more genes are TP53, SETD2, and SLC7A5, or mammalian orthologs thereof. In some embodiments, the one or more genes are GNA13, TP53, ENSCAFG00000001448, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are GNA13, TP53, and ENSCAFG00000001448, or mammalian orthologs thereof. In some embodiments, the one or more genes are EP3000, ABCC5, F0XL2, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are EP3000, ABCC5, and F0XL2, or mammalian orthologs thereof. In some embodiments, the one or more genes are PIK3CD, CREBBP, FBXW7, TRAF3, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are PIK3CD, CREBBP, FBXW7, and TRAF3, or mammalian orthologs thereof. In some embodiments, the one or more genes are N0TCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, KMT2D, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are N0TCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, and KMT2D, or mammalian orthologs.

[0267] In some embodiments, the one or more genes are CCND1, SMARCB1, FANCG, CDKN2B, MSH6, CCND3, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are CCND1, SMARCB1, FANCG, CDKN2B, MSH6, and CCND3, or mammalian orthologs.

[0268] In some embodiments, the one or more genes are TP53, SETD2, FXBW7, TRAF3, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are TP53, SETD2, FXBW7, and TRAF3, or mammalian orthologs thereof.

[0269] In some embodiments, the one or more genes are POTI , MYC, TP53, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are POTI, MYC, and TP53, or mammalian orthologs thereof. In some embodiments, the one or more genes are SETD2, TP53, TRAF3, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are SETD2, TP53, and TRAF3, or mammalian orthologs. In some embodiments, the one or more genes are TRAF3, PIK3CD, CREBBP, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are TRAF3, PIK3CD, and CREBBP, or mammalian orthologs thereof.

[0270] In some embodiments, the one or more genes are TRAF3, MAP3K14, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes areAttorney Ref: 42800-64265 / WO (OOIWO)TRAF3 and MAP3K14, or mammalian orthologs thereof. In some embodiments, the one or more genes are MYC, TBL1XR1, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are MYC and TBL1XR1, or mammalian orthologs thereof. In some embodiments, the one or more genes are MTOR, PIK3CD, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are MTOR and PIK3CD, or mammalian orthologs thereof. In some embodiments, the one or more genes are ARID 1 A, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are ARID1 A and CREBBP, or mammalian orthologs thereof. In some embodiments, the one or more genes are KMT2D, BCL11B, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are KMT2D and BCL1 IB, or mammalian orthologs thereof. In some embodiments, the one or more genes are TRAF3, KMT2D, mammalian orthologs, or any combination thereof. In some embodiments, the one or more genes are TRAF3 and KMT2D, or mammalian orthologs thereof. In some embodiments, the one or more genes are PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are PIK3CD and CREBBP, or mammalian orthologs thereof. In some embodiments, the one or more genes are CKIT, BRAF, mammalian orthologs thereof, or any combination thereof. In some embodiments, the one or more genes are CKIT and BRAF, or mammalian orthologs thereof.

[0271] In some embodiments, the subject has T-cell lymphomas (TCLs). In some embodiments, the subject with TCLs has one or mutations in PIK3CD, NOTCH2, KMT2C, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, the subject with TCLs has one or mutations in PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof. In some embodiments, the subject with TCLs has one or more mutations in SATB1 or a mammalian ortholog thereof. In some embodiments, the subject with TCLs has one or more mutations in MTOR, PIK3CD, mammalian orthologs thereof, or any combination thereof. In some embodiments, the subject with TCLs has one or more mutations in MTOR and P1K3CD, or mammalian orthologs thereof. In some embodiments, the subject with TCLs has one or more mutations in BCL1 IB or a mammalian ortholog thereof. In some embodiments, the subject with TCLs has one or more mutations in NOTCH2 or a mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (OOIWO)

[0272] In some embodiments, the subject has B-cell lymphomas (BCLs). In some embodiments, the subject with BCLs has one or more mutations in FBXW7, TRAF3, KMT2D, CCND 1 , mammalian orthologs thereof, or any combination thereof. In some embodiments, the subject with BCLs has one or more mutations in FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof. In some embodiments, the subject with BCLs has one or more mutations in POTI, MYC, TP53, mammalian orthologs thereof, or any combination thereof. In some embodiments, the subject with BCLs has one or more mutations in POTI , MYC, and TP53, or mammalian orthologs thereof. In some embodiments, the subject with BCLs has one or more mutations in TRAF3, MAP3K14, mammalian orthologs, or any combination thereof. In some embodiments, the subject with BCLs has one or more mutations in TRAF3 and MAP3K14, or mammalian orthologs thereof. In some embodiments, the subject with BCLs has one or more mutations in FBXW7, POTI, mammalian orthologs, or any combination thereof. In some embodiments, the subject with BCLs has one or more mutations in FBXW7 and POTI, or mammalian orthologs thereof. In some embodiments, the subject with BCLs has one or more mutations in MYC, TBL1XR1, mammalian orthologs, or any combination thereof. In some embodiments, the subject with BCLs has one or more mutations in MYC and TBL1XR1 , or mammalian orthologs thereof. In some embodiments, the subject with BCLs has one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, the subject with BCLs has one or more mutations in MEF2C or a mammalian ortholog thereof. In some embodiments, the subject with BCLs has one or more mutations in SETD2 or a mammalian ortholog thereof. In some embodiments, the subject with BCLs has one or more mutations in TP53 or a mammalian ortholog thereof.5.2.5. Additional parameters in analysis

[0273] In some embodiments, in step b) of the method, additional characteristics of the sample from the subject is considered for prediction of the treatment outcome. In some embodiments, in step b) of the method, additional characteristics of the subject is considered for prediction of the treatment outcome. In some embodiments, additional characteristics of the sample from the subject and the subject is considered for prediction of the treatment outcome.

[0274] In some embodiments, the additional characteristics comprise an immunophenotype of cells from the subject. In some embodiments, the cells from the subject are derived fromAttorney Ref: 42800-64265 / WO (OOIWO) the sample. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a tumor sample. In some embodiments, the immunophenotype identifies the cells from the subject by expression of one or more surface markers. In some embodiments, the one or more surface markers comprise cell surface receptors or cell surface ligands.

[0275] In some embodiments, the immunophenotype identifies the cells as B cells. In some embodiments, the cells are identified as B cells based on the expression of one or more surface markers selected from the group consisting of: IgM, HLA-DR, CD 19, CD20, CD21, CD40, IgM, CD30, CD38, CD138, IgG, CD45, CD184, TNFRSF17, CD21, CD27, CD69, CD95, CDld, CD43, CD23, IgD, CD5, and any combination thereof. In some embodiments, the immunophenotype identifies the cells as T cells. In some embodiments, the cells are identified as T cells based on the expression of one or more surface markers selected from the group consisting of: CD3, CD5, CD62L, CD197, CD8, IFNy, TNFa, EOMES, CD4, CD183, IL-2, IL-4, IL-12, IL-18, STAT4, STAT1, CD194, CD28, CD45, T-bet, CD184, CD365, GATA3, CD194, IL17A, TGFp, IL-6, CD185, CD183, IL-21, CD25, CD127, CD152, IL-10, FoxP3, STAT5, CD197, CD45, CD44, and any combination thereof. In some embodiments, the immunophenotype identifies the cells from the subject by expression of one or more surface markers selected from the group consisting of: CD21, CD20, CD3, CD4, CD8, CD5, and CD45.

[0276] In some embodiments, the immunophenotype identifies the cells from the subject as B-cell lymphoma cells. In some embodiments, the immunophenotype identifies the cells from the subject as BCL cells via expression of CD2, CD3, CD4, CD5, CD7, CD8, CD21, CD19, CD22, CD79a, CD10, Ki67, Pax-5, TdT, CD20, or any combination thereof. In some embodiments, the immunophenotype identifies the cells from the subject as T-cell lymphoma cells. In some embodiments, the immunophenotype identifies the cells from the subject as TCL cells via expression of CD2, CD3, CD4, CD8, CD5, CD45, CD10, or any combination thereof. In some embodiments, the immunophenotype identifies subtypes of TCL cells. In some embodiments, the subtype of TCL cells comprises helper- like CD4+ T cells, CD8+ cytotoxic-like T cells, CD45- T-zone lymphoma cells, or atypical T cell lymphoma cells. In some embodiments, the helper-like CD4+ T cells have a CD3+ / CD4+ / CD8- expression portfolio. In some embodiments, CD8+ cytotoxic-like T cells have a CD3+ / CD4- / CD8+ expression portfolio. In some embodiments, the atypical T cell lymphoma cells comprise double negative T cells, double positive T cells, or aberrant (e.g., CD3-) T cells. In someAttorney Ref: 42800-64265 / WO (OOIWO) embodiments, the double negative T cells have a CD3+ / CD4- / CD8- expression portfolio. In some embodiments, the double positive T cells have CD3+ / CD4+ / CD8+ expression portfolio. In some embodiments, the CD3- T cells have a CD3- / CD4+ / CD8- expression portfolio or the CD3- T cells have a CD3- / CD4- / CD8- / CD5+ expression portfolio.

[0277] In some embodiments, the additional characteristics comprise phenotypic characteristics of the cells. In some embodiments, the phenotypic characteristics of the cells comprise the size of the cells. In some embodiments, the size of the cells is small, medium, or large. In some embodiments, the BCL cells are further characterized by cell size. In some embodiments, the BCL cells comprise small cell BCL cells, medium cell BCL cells, large cell BCL cells, or diffuse large cell BCL cells.

[0278] In some embodiments, the additional characteristics comprise ex- vivo drug sensitivity of the cells from the subject. In some embodiments, the cells are exposed to one or more drugs to determine the sensitivity of the cells to the one or more drugs. In some embodiments, the cells are sensitive to the one or more drugs. In some embodiments, cells that are sensitive to the one or more drugs are lysed following treatment with the one or more drugs. In some embodiments, the cells are resistant to the one or more drugs. In some embodiments, cells that are resistant to the one or more drugs may not be lysed following treatment with the one or more drugs.

[0279] In some embodiments, the ex-vivo drug sensitivity of the cells from the subject is measured for one or more drugs (e.g., one or more treatment regimens) selected from the group consisting of: Actinomycin, Docetaxel, Doxorubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Doxycycline, Erythromycin, Itraconazole, Ketoconazole, Levofloxacin, Sparfloxacin, Tetracycline, Amitriptyline, Paroxetine, Venlafaxine, Aldosterone, Cortisol, Dexamethasone, Cyclophosphamide, Ethoposide, Bleomycin, Ifofamide, Cisplatin, Vincristine, Chlorambucil, Methotrexate, Gemcitabine, Prednisone, Bendamustine, Cytarabine, Carmustine, Decarbazine, Procarbazine, L-asparaginase, Rituximab, Lomustine, Mechlorethamine, Melphalan, Temozolomide, Midostaurin, Nelarabine, Ponatinib, Rabacfosadine, Hydrocortisone, Methylprednisolone, Triamcinolone, Butorphanol, Loperamide, Methadone, Morphine, Pentazocine, Amiodarone, Carvedilol, Digoxin, Diltiazem, Nicardipine, Quinidine, Talinolol, Verapamil, Cyclosporine, Tacrolimus, Ivermectin, Milbemycin, Selamectin, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Brentuximab Vedotin, Loncastuximab Tesirine-lpyl, Mosunetuzumab-axgb,Attorney Ref: 42800-64265 / WO (001WO)Epcoritamab-bysp, Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Lisocabtagene Maraleucel, Tisagenlecleucel, Azacitidine, Busulfan, Dasatinib, Daunorubicin, Decitabine, Fludarabine, Gilteritinib, Ibrutinib, Idarubicin, Ifosfamide, Imatinib, Sorafenib, Venetoclax, Acalabrutinib, Apatinib, Belinostat, Bortezomib, Cabozantinib, Crizotinib, Darafenib, Everolimus, Idelalisib, Romidepsin, Ruxolitinib, Temsirolimus, Tofacitinib, Trametinib, Vemurafenib, Vorinostat, Nivolumab, Pembrolizumab, Denileukin Diftitox, Lenalidomide, Interferon Alfa-2b, Brentuximab Vedotin, Ibritumonmab Tiuxetan, Ofatumumab, Obinutuzumab, Polatuzumab, Polatuzumab Vedotin-Piiq, Rituximab, Tafasitamab, Ibritumomab Tiuxetan, corticosteroid hormones, somatostatin analogues, and any combination thereof.

[0280] In some embodiments, the ex-vivo drug sensitivity of the cells from the subject is measured for one or more drugs selected from the group consisting of: Actinomycin, Docetaxel, Doxorubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Doxycycline, Erythromycin, Itraconazole, Ketoconazole, Levofloxacin, Sparfloxacin, Tetracycline, Amitriptyline, Paroxetine, Venlafaxine, Aldosterone, Cortisol, Dexamethasone, Hydrocortisone, Methylprednisolone, Triamcinolone, Butorphanol, Loperamide, Methadone, Morphine, Pentazocine, Amiodarone, Carvedilol, Digoxin, Diltiazem, Nicardipine, Quinidine, Talinolol, Verapamil, Cyclosporine, Tacrolimus, Ivermectin, Milbemycin, Selamectin, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and any combination thereof.

[0281] In some embodiments, the ex-vivo drug sensitivity of the cells is tested for between one different treatment regimen to 100 treatment regimens. In some embodiments, the ex- vivo drug sensitivity of the cells is tested for at least or up to one treatment regimen, at least or up to two treatment regimens, at least or up to three treatment regimens, at least or up to four treatment regimens, at least or up to five treatment regimens, at least or up to six treatment regimens, at least or up to seven treatment regimens, at least or up to eight treatment regimens, at least or up to nine treatment regimens, at least or up to ten treatment regimens, at least or up to 20 treatment regimens, at least or up to 30 treatment regimens, at least or up to 40 treatment regimens, at least or up to 50 treatment regimens, at least or up to 60 treatment regimens, at least or up to 70 treatment regimens, at least or up to 80 treatment regimens, at least or up to 90 treatment regimens, or at least or up to 100 treatment regimens.Attorney Ref: 42800-64265 / WO (OOIWO)

[0282] In some embodiments, the additional characteristics comprise clinical data from the subject. In some embodiments, the clinical data of the subject is selected from the group consisting of: age of the subject, biological sex of the subject, surgical history of the subject, current medications taken by the subject, a stage of a cancer, length of time since diagnosis of the cancer, weight of the subject, height of the subject, previous treatment regimens administered to the subject, treatment outcomes of the previous treatment regimens administered to the subject, body temperature of the subject, pulse rate of the subject, respiration rate of the subject, blood pressure of the subject, allergies of the subject, international travel history of the patient, pregnancy status of the subject, menopause status of the subject, preexisting conditions of the subject, laboratory testing results, diagnostic images of the subject, familial history of diseases or disorders, current diet of the subject, exercise information of the subject, complete blood counts of the subject, age of the subject, comorbidities of the subject, current treatment regimen of the subject, blood chemistry of the subject, naive disease or disorder status of the subject, relapsed disease or disorder status of the subject, diabetes status of the subject, concurrent leukemia status of the subject, and any combination thereof.

[0283] In some embodiments, the clinical data of the subject is selected from the group consisting of: a stage of a cancer, length of time since diagnosis of the cancer, previous treatment regimens administered to the subject, treatment outcomes of the previous treatment regimens administered to the subject, and any combination thereof. In some embodiments, the clinical data of the subject is the stage of a cancer. In some embodiments, the clinical data of the subject is length of time since diagnosis of the cancer. In some embodiments, the clinical data of the subject is previous treatment regimens administered to the subject. In some embodiments, the clinical data of the subject is treatment outcomes of the previous treatment regimens administered to the subject.

[0284] In some embodiments, the additional characteristics comprise information regarding cellular functions of the cells from the subject. In some embodiments, the cellular functions of the cells are apoptosis, migration, autophagy, cell metabolism, cell proliferation, cell viability, cytotoxicity ability, protein synthesis, oxidative stress, or any combination thereof. In some embodiments, the cellular function of the cells is apoptosis. In some embodiments, the cellular function of the cells is migration. In some embodiments, the cellular function of the cells is autophagy. In some embodiments, the cellular function of the cells is cellAttorney Ref: 42800-64265 / WO (OOIWO) metabolism. In some embodiments, the cellular function of the cells is cell proliferation. In some embodiments, the cellular function of the cells is cell viability. In some embodiments, the cellular function of the cells is cytotoxicity ability. In some embodiments, the cellular function of the cells is protein synthesis. In some embodiments, the cellular function of the cells is oxidative stress.5.2.6. Additional steps for treating the subject with cancer

[0285] In some embodiments, the method further comprises d) selecting a treatment regimen based on the prediction. In some embodiments, the treatment regimen is selected based on the presence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, the treatment regimen is selected based on the absence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, the treatment regimen is selected based on (i) the presence of the one or more mutations and (ii) the absence of the one or more mutations in the sequences of the one or more genes in the subject.

[0286] Alternatively, in some embodiments, a treatment regimen is not selected based on the prediction. In some embodiments, a treatment regimen is not selected based on the presence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, a treatment regimen is not selected based on the absence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, a treatment regimen is not selected based on the absence of the one or more mutations in the sequences of the one or more genes in the subject. In some embodiments, a treatment regimen is not selected based on (i) the presence of the one or more mutations and (ii) the absence of the one or more mutations in the sequences of the one or more genes in the subject.

[0287] In some embodiments, the method further comprises e) treating the subject by the selected treatment regimen. In some embodiments, the method further comprises e) causing to treat the subject by the selected treatment regimen. In some embodiments, the method further comprising administrating the selected treatment regimen to the subject. In some embodiments, the administration route of the selected treatment regimen is one or more administration routes selected from the group consisting of: oral, intravenous, transdermal, sublingual, buccal, nasal, intraperitoneal, ocular, rectal, intravaginal, topical, intrathecal, intramuscular, subcutaneous, parenteral, enteral, inhalation, intradermal, and any combinationAttorney Ref: 42800-64265 / WO (OOIWO) thereof. In some embodiments, the treatment regimen is intravenously administered to the subject. In some embodiments, the treatment regimen is orally administered to the subject. In some embodiments, the treatment regimen is subcutaneously administered to the subject.5.2.7. Treatment Regimens

[0288] In some embodiments, the subject is administered the treatment regimen. In some embodiments, the treatment regimen is selected from the group consisting of: chemotherapy, immunotherapy, radiation, hormone therapy, surgery, bone marrow transplant, and any combination thereof.

[0289] In some embodiments, the treatment regimen is chemotherapy. In some embodiments, the chemotherapy is selected from the group consisting of: cyclophosphamide, etoposide, bleomycin, ifofamide, cisplatin, doxorubicin, vincristine, chlorambucil, methotrexate, gemcitabine, prednisone, bendamustine, cytarabine, carmustine, dacarbazine, procarbazine, and any combination thereof. In some embodiments, the chemotherapy is a chemotherapy regimen. In some embodiments, the chemotherapy regimen is selected from the group consisting of: a cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) regimen; a L-asparaginase CHOP (L-CHOP) regimen; a rituximab CHOP (R-CHOP) regimen, a lomustine (CCNU) regimen; a rabacfocsadine (Tanovea) regimen; a mustargen, vinca alkaloids, procarbazine, and corticosteroids (MOPP) regimen; a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen; a CCNU and vincristine (LOPP) regimen; a cyclophosphamide, vincristine, and prednisone (COP) regimen; and any combination thereof. In some embodiments, the chemotherapy regimen is a combination of one or more different chemotherapy drugs. In some embodiments, the one or more different chemotherapy drugs comprise at least or up to one chemotherapy drug, at least or up to two different chemotherapy drugs, at least or up to three different chemotherapy drugs, at least or up to four different chemotherapy drugs, at least or up to five different chemotherapy drugs, at least or up to six different chemotherapy drugs, at least or up to seven different chemotherapy drugs, at least or up to eight different chemotherapy drugs, at least or up to nine different chemotherapy drugs, or at least or up to ten different chemotherapy drugs. In some embodiments, the treatment regimen comprises one or more different chemotherapy regimens. In some embodiments, the treatment regimen comprises at least or up to one chemotherapy regimen, at least or up to two chemotherapy regimens, at least or up to three chemotherapy regimens, at least or up to four chemotherapy regimens, atAttorney Ref: 42800-64265 / WO (OOIWO) least or up to five chemotherapy regimens, at least or up to six chemotherapy regimens, at least or up to seven chemotherapy regimens, at least or up to eight chemotherapy regimens, at least or up to nine chemotherapy regimens, or at least or up to ten chemotherapy regimens.

[0290] In some embodiments, the treatment regimen is immunotherapy. In some embodiments, the immunotherapy is selected from the group consisting of: antibody-drug conjugates (ADC), bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, cytokines, immunomodulatory drugs, monoclonal antibodies, radioimmunotherapy, and any combination thereof. In some embodiments, the immunotherapy is ADC. In some embodiments, the ADC is Brentuximab Vedotin, Loncastuximab Tesirine-lpyl, or any combination thereof. In some embodiments, the immunotherapy is bispecific antibodies. In some embodiments, the bispecific antibodies are Mosunetuzumab-axgb, Epcoritamab-bysp, or any combination thereof. In some embodiments, the immunotherapy is CAR T cells. In some embodiments, the CAR T cells are Axicabtagene Ciloleucel, Brexucabtagene Autoleucel, Lisocabtagene Maraleucel, Tisagenlecleucel, or any combination thereof. In some embodiments, the immunotherapy is checkpoint inhibitors. In some embodiments, the checkpoint inhibitors are Nivolumab, Pembrolizumab, or any combination thereof. In some embodiments, the immunotherapy is cytokines. In some embodiments, the cytokines are Denileukin Diftitox. In some embodiments, the immunotherapy is immunomodulatory drugs. In some embodiments, the immunomodulatory drugs are Lenalidomide, Interferon Alfa-2b, or any combination thereof. In some embodiments, the immunotherapy is monoclonal antibodies. In some embodiments, the monoclonal antibodies are Brentuximab Vedotin, Ibritumonmab Tiuxetan, Ofatumumab, Obinutuzumab, Polatuzumab, Polatuzumab Vedotin-Piiq, Rituximab, Tafasitamab, or any combination thereof. In some embodiments, the immunotherapy is radioimmunotherapy. In some embodiments, the radioimmunotherapy is Ibritumomab Tiuxetan. In some embodiments, the treatment regimen comprises one or more different immunotherapies. In some embodiments, the treatment regimen comprises at least or up to one immunotherapy, at least or up to two immunotherapies, at least or up to three immunotherapies, at least or up to four immunotherapies, at least or up to five immunotherapies, at least or up to six immunotherapies, at least or up to seven immunotherapies, at least or up to eight immunotherapies, at least or up to nine immunotherapies, or at least or up to ten immunotherapies .Attorney Ref: 42800-64265 / WO (001WO)

[0291] In some embodiments, the treatment regimen is hormone therapy. In some embodiments, the hormone therapy is corticosteroid hormones, somatostatin analogues, or any combination thereof.

[0292] In some embodiments, the treatment regimen is administered to the subject between one time to 100 times. In some embodiments, the treatment regimen is administered to the subject at least or up to one time, at least or up to two times, at least or up to three times, at least or up to four times, at least or up to five times, at least or up to six times, at least or up to seven times, at least or up to eight times, at least or up to nine times, at least or up to ten times, at least or up to 15 times, at least or up to 20 times, at least or up to 25 times, at least or up to 30 times, at least or up to 35 times, at least or up to 40 times, at least or up to 45 times, at least or up to 50 times, at least or up to 55 times, at least or up to 60 times, at least or up to 65 times, at least or up to 70 times, at least or up to 75 times, at least or up to 80 times, at least or up to 85 times, at least or up to 90 times, at least or up to 95 times, or at least or up to 100 times.

[0293] In some embodiments, the treatment regimen is administered one or more times a day. In some embodiments, the treatment regimen is administered at least or up to one time a day, at least or up to two times a day, at least or up to three times a day, at least or up to four times a day, at least or up to five times a day, at least or up to six times a day, at least or up to seven times a day, at least or up to eight times a day, at least or up to nine times a day, or at least or up to ten times a day. In some embodiments, the treatment regimen is administered daily, every other day, every two days, every three days, every four days, every five days, every six days, weekly, biweekly, monthly, every two months, every three months, every four months, every five months, every six months, or yearly.

[0294] In some embodiments, the treatment regimen can be any combination of any of the treatment regimens disclosed herein.

[0295] In some embodiments, in step c), a positive response to a CHOP regimen or a L- CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL. In some embodiments, in step d), a CHOP regimen or a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a CHOPAttorney Ref: 42800-64265 / WO (OOIWO) regimen and a L-CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof and (ii) the subject has BCL. In some embodiments, in step d), a CHOP regimen and a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof, and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a CHOP regimen and a L-CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL. Tn some embodiments, in step d), a CHOP regimen and a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL.

[0296] In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, an increase in DFS, an increase in TTP, an increase in EFS, an increase in TTNT, or any combination thereof. In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, or any combination thereof. In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS. In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise an increase in OS. In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise an increase in DOR. In some embodiments, the positive response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in TRAF3, FBXW7, mammalian orthologs thereof, or any combination thereof comprise a decrease in TTR.Attorney Ref: 42800-64265 / WO (OOIWO)

[0297] In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step d), a CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has one or more mutations in FBXW7 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step d), a CHOP regimen is selected when (i) the subject has one or more mutations in FBXW7 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL. In some embodiments, in step d), a CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL.

[0298] In some embodiments, in step c), a positive response to a L-CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 or mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step d), a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a L-CHOP regimen is predicted when (i) the subject has one or more mutations in FBXW7 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step d), a L-CHOP regimen is selected when (i) the subject has one or more mutations in FBXW7 or a mammalian ortholog thereof and (ii) the subject has BCL. In some embodiments, in step c), a positive response to a L-CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL. In some embodiments, in step d), a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has BCL.

[0299] In some embodiments, in step c), a positive response to a CHOP regimen or a L- CHOP regimen is predicted when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step c), a positive response to a CHOP regimen or a L-CHOP regimen is predicted when (i) the subject has one or moreAttorney Ref: 42800-64265 / WO (001WO) mutations in TRAF3 or a mammalian ortholog and (ii) the subject has BCL or TCL. In some embodiments, in step d), a CHOP regimen or a L-CHOP regimen is selected when the subject has one or more mutations mutation in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step c), to a CHOP regimen or a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog and (ii) the subject has BCL or TCL. In some embodiments, the one or more mutations in TRAF3 comprise a c.I267C>T mutation. In some embodiments, the c. !267C>T mutation generates a truncation of the TRAF3 protein at an arginine at position 423. In some embodiments, the c.! 267C>T mutation is located in the meprin and TRAF homology (MATH) domain. In some embodiments, the c.!267C>T mutation is located at the N-terminal end of the MATH domain. In some embodiments, the one or more mutations in TRAF3 are located in a domain for trimerization of TRAF3.

[0300] In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has TCL. In some embodiments, in step d), a CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has TCL. In some embodiments, in step c), a positive response to a L- CHOP regimen is predicted when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has TCL. In some embodiments, in step d), a L-CHOP regimen is selected when (i) the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof and (ii) the subject has TCL.

[0301] In some embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, an increase in DFS, an increase in TTP, an increase in EFS, an increase in TTNT, or any combination thereof. In some embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, or any combination thereof. In some embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises an increase in PFS. In some embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises an increase in OS. In someAttorney Ref: 42800-64265 / WO (OOIWO) embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises an increase in DOR. In some embodiments, the positive response to the CHOP regimen when the subject has one or more mutations in TRAF3 or a mammalian ortholog thereof comprises a decrease in TTR.

[0302] In some embodiments, in step c), a positive response to a CHOP regimen or a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof. In some embodiments, in step d), a CHOP regimen or a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof.

[0303] In some embodiments, the positive response to the CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, an increase in DFS, an increase in TTP, an increase in EFS, an increase in TTNT, or any combination thereof. In some embodiments, the positive response to a CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, or any combination thereof. In some embodiments, the positive response to a CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS. In some embodiments, the positive response to a CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise an increase in OS. In some embodiments, the positive response to a CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise an increase in DOR. In some embodiments, the positive response to a CHOP regimen, a Tanovea-based regimen, or any combination thereof when the subject has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof comprise a decrease in TTR.Attorney Ref: 42800-64265 / WO (001WO)

[0304] In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in KMT2D or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP regimen is selected when the subject has (i) BCL and (ii) one or more mutations in KMT2D or a mammalian ortholog thereof. In some embodiments, in step c), a positive response to a CHOP regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3, and KMT2D, or mammalian orthologs thereof. In some embodiments, in step d), a CHOP regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof.

[0305] In some embodiments, in step c), a positive response to a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step d), a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 or a mammalian ortholog thereof. In some embodiments, in step c), a positive response to a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in KMT2D or a mammalian ortholog thereof. In some embodiments, in step d), a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in KMT2D or a mammalian ortholog thereof. In some embodiments, in step c), a positive response to Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof. In some embodiments, in step d), a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof.

[0306] In some embodiments, in step c), a positive response to a CHOP regimen and a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3, KMT2D, mammalian orthologs thereof, or any combination thereof. In some embodiments, in step d), a CHOP regimen and a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3, KMT2D,Attorney Ref: 42800-64265 / WO (OOIWO) mammalian orthologs thereof, or any combination thereof. In some embodiments, in step c), a positive response to a CHOP regimen or a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof. In some embodiments, in step d), a CHOP regimen or a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof. In some embodiments, in step c), a positive response to a CHOP regimen and a Tanovea-based regimen is predicted when (i) the subject has BCL and (ii) has one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof. In some embodiments, in step d), a CHOP regimen and a Tanovea-based regimen is selected when the subject has (i) BCL and (ii) one or more mutations in TRAF3 and KMT2D, or mammalian orthologs thereof.

[0307] In some embodiments, in step c), a negative response to a CHOP-like regimen, a lomustine-containing regimen (CCNU), or any combination thereof is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, a CHOP-like comprises a CHOP regimen, a L-CHOP regimen, a R-CHOP regiment, or any combination thereof. In some embodiments, in step d), a CHOP-like regimen, a lomustine-containing regimen, or any combination thereof is not selected when (i) the subject has TCL and (ii) has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof.

[0308] In some embodiments, the negative response to a CHOP-like regimen, a CCNU- containing regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise a decrease in PFS, a decrease in OS, a decrease in DOR, an increase in TTR, a decrease in DFS, a decrease in TTP, a decrease in EFS, a decrease in TTNT, or any combination thereof. In some embodiments, the negative response to a CHOP-like regimen, a CCNU-containing regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise a decrease in PFS, a decrease in OS, a decrease in DOR, an increase in TTR, or any combination thereof. In some embodiments, the negative response to a CHOP-like regimen, a CCNU-containing regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise a decrease in PFS. In some embodiments, the negative response to a CHOP-like regimen, a CCNU-Attorney Ref: 42800-64265 / WO (001WO) containing regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise a decrease in OS. In some embodiments, the negative response to a CHOP-like regimen, a CCNU-containing regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise a decrease in DOR. In some embodiments, the negative response to the CHOP regimen, a L-CHOP regimen, or any combination thereof when the subject has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof comprise an increase in TTR.

[0309] In some embodiments, in step c), a negative response to a CHOP-like regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP-like regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in PIK3CD or a mammalian ortholog thereof. In some embodiments, in step c), a negative response to a CHOP-like regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in CREBBP or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP-like regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in CREBBP or a mammalian ortholog thereof.

[0310] In some embodiments, in step c), a negative response to a CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in PIK3CD or a mammalian ortholog thereof. In some embodiments, in step c), a negative response to a CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in CREBBP or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in CREBBP or a mammalian ortholog thereof.

[0311] In some embodiments, in step c), a negative response to a L-CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D or a mammalian ortholog thereof. In some embodiments, in step d), a L-CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in PIK3CD or a mammalian ortholog thereof. In some embodiments, in step c), a negative response to a L-Attorney Ref: 42800-64265 / WO (OOIWO)CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in CREBBP or a mammalian ortholog thereof. In some embodiments, in step d), a L- CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in CREBBP or a mammalian ortholog thereof.

[0312] In some embodiments, in step c), a negative response to a R-CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D or a mammalian ortholog thereof. In some embodiments, in step d), a R-CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in PIK3CD or a mammalian ortholog thereof. In some embodiments, in step c), a negative response to a R- CHOP regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in CREBBP or a mammalian ortholog thereof. In some embodiments, in step d), a R-CHOP regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in CREBBP or a mammalian ortholog thereof.

[0313] In some embodiments, in step c), a negative response to a CCNU-containing regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D or a mammalian ortholog thereof. In some embodiments, in step d), a CCNU-containing regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in PIK3CD or a mammalian ortholog thereof. In some embodiments, in step c), a negative response to a CCNU-containing regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in CREBBP or a mammalian ortholog thereof. In some embodiments, in step d), a CCNU-containing regimen is not selected when (i) the subject has TCL and (ii) has one or more mutation in CREBBP or a mammalian ortholog thereof.

[0314] In some embodiments, in step c), a negative response to a CHOP-like regimen, a CCNU-containing regimen, or any combination thereof is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D and CREBBP, or mammalian orthologs thereof. In some embodiments, in step d), a CHOP-like regimen, a CCNU-containing regimen, or any combination thereof is not selected when (i) the subject has TCL and (ii) has one or more mutations in PIK3CD and CREBBP, or mammalian orthologs thereof. In some embodiments, in step c), a negative response to a CHOP-like regimen and a CCNU- containing regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, in step d), a CHOP-like regimen and a CCNU-containing regimen, orAttorney Ref: 42800-64265 / WO (OOIWO) any combination thereof is not selected when (i) the subject has TCL and (ii) has one or more mutations in PIK3CD, CREBBP, mammalian orthologs thereof, or any combination thereof. In some embodiments, in step c), a negative response to a CHOP-like regimen and a CCNU- containing regimen is predicted when (i) the subject has TCL and (ii) has one or more mutations in PIK3D and CREBBP, or mammalian orthologs thereof. In some embodiments, in step d), a CHOP-like regimen and a CCNU-containing regimen is not selected when (i) the subject has TCL and (ii) has one or more mutations in PIK3CD and CREBBP, or mammalian orthologs thereof.

[0315] In some embodiments, in step c), a positive response to a CHOP regimen is predicted when the subject has (i) TCL and (ii) one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof. In some embodiments, in step d), a CHOP regimen is selected when the subject has (i) TCL and (ii) one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof.

[0316] In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, an increase in DFS, an increase in TTP, an increase in EFS, an increase in TTNT, or any combination thereof. In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS, an increase in OS, an increase in DOR, a decrease in TTR, or any combination thereof. In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise an increase in PFS. In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise an increase in OS. In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise an increase in DOR. In some embodiments, the positive response to a CHOP regimen when the subject has one or more mutations in KMT2C, NOTCH2, mammalian orthologs thereof, or any combination thereof comprise a decrease in TTR.Attorney Ref: 42800-64265 / WO (OOIWO)

[0317] In some embodiments, in step c), a positive response to a CHOP regimen is predicted when the subject has (i) TCL and (ii) one or more mutations in KMT2C or a mammalian ortholog thereof. In some embodiments, in step d), a CHOP regimen is selected when the subject has (i) TCL and (ii) one or more mutations in KMT2C or a mammalian ortholog. In some embodiments, in step c), a positive response to a CHOP regimen is pre...

Claims

Attorney Ref: 42800-64265 / WO (OOIWO)WHAT IS CLAIMED IS:

1. A method for treating a subject with lymphoma, comprising: a) obtaining sequence information of one or more genes in the subject, wherein the one or more genes comprise: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and / or mammalian orthologs thereof; b) based on the sequence information, predicting a treatment outcome of the subject; and c) providing information related to the prediction to (i) the subject or (ii) a care giver or a medical provider for the subject for use in treatment of the subject.

2. The method of claim 1, wherein the one or more additional genes are selected from KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

3. The method of claim 1 , further comprising: d) selecting a treatment regimen based on the prediction.

4. The method of claim 3, further comprising: e) causing to treat the subject by the selected treatment regimen.

5. The method of any one of claims 1-4, further comprising a preceding step of generating the sequence information by analyzing a sample of the subject.

6. The method of claim 5, wherein the step of generating the sequence information comprises contacting the sample with one or more probes, thereby inducing hybridization of one or more target polynucleotides in the sample with the one or more probes, wherein each of the one or more probes is configured to bind to a sequence specific to the one or more genes.Attorney Ref: 42800-64265 / WO (OOIWO)7. The method of claim 6, wherein each of the one or more target polynucleotides comprises the sequence specific to the one or more genes.

8. The method of claim 7, wherein the one or more target polynucleotides comprises one or more mutations.

9. The method of any one of claims 6-8, wherein the step of generating the sequence information further comprises enriching the one or more target polynucleotides hybridized with the one or more probes from the sample.

10. The method of claim 9, wherein the enriching step is performed by reacting the one or more probes with a bead and isolating the bead, thereby obtaining enriched target polynucleotides, wherein the bead is configured to bind to the one or more probes.

11. The method of claim 10, wherein the bead is a magnetic streptavidin bead.

12. The method of any one of claims 6-11, wherein the step of generating the sequence information further comprises amplifying the one or more target polynucleotides hybridized with the one or more probes or the enriched target polynucleotides.

13. The method of claim 12, wherein the one or more target polynucleotides or the enriched polynucleotides are amplified via a polymerase.

14. The method of claim 13, wherein the polymerase is an RNA polymerase or a DNA polymerase.

15. The method of any one of claims 6-14, wherein the step of generating the sequence information further comprises sequencing (i) the one or more target polynucleotides hybridized with the one or more probes, (ii) the enriched target polynucleotides, or (iii) enriched and amplified target polynucleotides.

16. The method of claim 15, wherein the sequencing is performed by next generation sequencing.Attorney Ref: 42800-64265 / WO (OOIWO)17. The method of claim 15 or 16, wherein the step of sequencing further comprises identifying one or more mutations in the one or more genes.

18. The method of claim 5, wherein the step of generating the sequence information comprises contacting the sample with one or more pairs of primers, thereby inducing hybridization of one or more target polynucleotides in the sample with the one or more pairs of primers, wherein each of the one or more pairs of primers is configured to bind to a sequence specific to the one or more genes.

19. The method of claim 18, wherein each of the one or more target polynucleotides comprises the sequence specific to the one or more genes.

20. The method of claim 18 or 19, wherein the step of generating the sequence information further comprises amplifying the one or more target polynucleotides hybridized with the one or more pairs of primers.

21. The method of claim 20, wherein the one or more primers are extended via a polymerase.

22. The method of claim 21 , wherein the polymerase is an RNA polymerase or a DNA polymerase.

23. The method of claim 21 or 22, wherein the polymerase extends the one or more pairs of primers using the one or more target polynucleotides as a template.

24. The method of any one of claims 20-23, wherein the amplifying step comprises performing polymerase chain reaction (PCR) or quantitative PCR.

25. The method of any one of claims 20-24, wherein the amplifying step comprises quantitative PCR (qPCR).

26. The method of claim 25, wherein the qPCR is performed in the presence of a mutantspecific probe configured to bind to one of the target polynucleotides with a mutation.Attorney Ref: 42800-64265 / WO (OOIWO)27. The method of claim 26, wherein the mutant-specific probe is labeled with a fluorescent dye and a quencher.

28. The method of claim 26 or 27, wherein the qPCR is performed in the presence of a control probe configured to bind to one of the target polynucleotides without the mutation.

29. The method of claim 26, wherein the control probe is labeled with a different fluorescent dye and a different quencher.

30. The method of any one of claim 25-29, further comprising detecting fluorescent signals from the mutant-specific probe and / or the control probe, thereby determining presence, absence, or relative abundance of the mutation in the one of the target polynucleotide.

31. The method of any one of claims 18-24, wherein the step of generating the sequence information further comprises sequencing the amplified target polynucleotides.

32. The method of claim 31, wherein the sequencing is performed by next generation sequencing.

33. The method of claim 31 or 32, wherein the step of sequencing further comprises identifying one or more mutations in the one or more genes.

34. The method of any one of claims 20-33, wherein the amplified target polynucleotides comprise the one or more mutations in the one or more genes.

35. The method of claim 33 or 34, wherein each of the one or more pairs of primers is configured to amplify the one or more target polynucleotides that comprise the one or more mutations.

36. The method of any one of claims 1-35, wherein the one or more genes are 20 different genes, 19 different genes, 18 different genes, 17 different genes, 16 different genes, 15 different genes, 14 different genes, 13 different genes, 12 different genes, 11 different genes, 10 , 9 different genes, 8 different genes, 7 different genes, 6 different genes, 5 different genes, 4 different genes, 3 different genes, 2 different genes or a single gene selected from the groupAttorney Ref: 42800-64265 / WO (OOIWO) consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

37. The method of any one of claims 1-36, wherein the one or more genes are the first 20 genes, the first 19 genes, the first 18 genes, the first 17 genes, the first 16 genes, the first 15 genes, the first 14 genes, the first 13 genes, the first 12 genes, the first 11 genes, the first 10 genes, the first 9 genes, the first 8 genes, the first 7 genes, the first 6 genes, the first 5 genes, the first 4 genes, the first 3 genes, or the first 2 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs.

38. The method of any one of claims 1-36, wherein the one or more genes are KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1 A, CREBBP, and TP53, or mammalian orthologs thereof.

39. The method of any one of claims 1-36, wherein the one or more genes are PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof.

40. The method of claim 39, wherein the subject has T-cell lymphomas (TCLs).

41. The method of any one of claims 1-36, wherein the one or more genes are FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof.

42. The method of claim 41, wherein the subject has B-cell lymphomas (BCLs).

43. The method of any one of claims 1-36, wherein the one or more genes are TRAF3 and FBXW7, or mammalian orthologs thereof.

44. The method of any one of claims 1-37, wherein the one or more genes are TRAF3 and KMT2D, or mammalian orthologs thereof.

45. The method of any one of claims 1-37, wherein the one or more genes are PIK3CD and CREBBP, or mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (OOIWO)46. The method of any one of claims 1-37, wherein the one or more genes are CREBBP or a mammalian ortholog thereof.

47. The method of any one of claims 1-37, wherein the one or more genes are TRAF3 or a mammalian ortholog thereof.

48. The method of any one of claims 1-37, wherein the one or more genes are FBXW7 or a mammalian ortholog thereof.

49. The method of any one of claims 1-37, wherein the one or more genes are CCND1 or a mammalian ortholog thereof.

50. The method of any one of claims 1 -37, wherein the one or more genes are KMT2C or a mammalian ortholog thereof.

51. The method of any one of claims 1-37, wherein the one or more genes are NOTCH2 or a mammalian ortholog thereof.

52. The method of any one of claims 1-37, wherein the one or more genes are PIK3CD or a mammalian ortholog thereof.

53. The method of any one of claims 1-37, wherein the one or more genes are selected from SETD2, TP53, and TRAF3, or mammalian orthologs thereof.

54. The method of any one of claims 1-37, wherein the one or more genes are selected from a-d, wherein a-d are: a. KMT2C and NOTCH2, or mammalian orthologs thereof; b. KMT2D and KMT2C, or mammalian orthologs thereof; c. KMT2C and BCL1 IB, or mammalian orthologs thereof; or d. KMT2D and NOTCH2, or mammalian orthologs thereof.

55. The method of any one of claims 1-37, wherein the one or more genes are selected from a-e, wherein a-e are: a. TRAF3 and SETD2 or mammalian orthologs thereof; b. TRAF3 and POTI, or mammalian orthologs thereof;Attorney Ref: 42800-64265 / WO (OOIWO) c. TRAF3 and TBL1XR1, or mammalian orthologs thereof; d. TP53 and SETD2, or mammalian orthologs thereof; or e. POTI and FBXW7, or mammalian orthologs thereof.

56. The method of any one of claims 1-37, wherein the one or more genes are selected from a-j, wherein a-j are: a. MTOR, KLF4, VEGFA or mammalian orthologs thereof; b. MTOR. KLF4, ITK or mammalian orthologs thereof; c. CCND1, KMT2D, TP53, ARID 1 A or mammalian orthologs thereof; d. CCND1, TNFRSF11A, SLC19A1, TP53 or mammalian orthologs thereof; e. CCND1, TP53 or mammalian orthologs thereof; f. TP53, SETD2, SLC7A5 or mammalian orthologs thereof; g. GNA13, TP53, ENS CAFG00000001448 or mammalian orthologs thereof; h. EP3000, ABCC5, F0XL2 or mammalian orthologs thereof; i. PIK3CD, CREBBP, FBXW7, TRAF3 or mammalian orthologs thereof; or j. N0TCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, KMT2D or mammalian orthologs thereof.

57. The method of any one of claims 3-56, wherein the treatment regimen is selected from the group consisting of: chemotherapy, immunotherapy, radiation, hormone therapy, surgery, bone marrow transplant, and any combination thereof.

58. The method of claim 57, wherein the chemotherapy is selected from the group consisting of: a cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) regimen, a L-asparaginase CHOP (L-CHOP) regimen, a rituximab CHOP (R-CHOP) regimen, a lomustine (CCNU) regimen, a rabacfocsadine regimen, a mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen, and any combination thereof.

59. The method of any one of claims 1-58, wherein in step c), a positive response to a CHOP regimen or a L-CHOP regimen is predicted when (i) the subject has mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has B-cell lymphoma (BCL).Attorney Ref: 42800-64265 / WO (OOIWO)60. The method of any one of claims 3-59, wherein in step d), a CHOP regimen or a L- CHOP regimen is selected when (i) the subject has mutations in TRAF3 and FBXW7, or mammalian orthologs thereof, and (ii) the subject has B-cell lymphoma (BCL).

61. The method of any one of claims 1-60, wherein in step c), a positive response to a CHOP regimen or a L-CHOP regimen is predicted when the subject has a mutation in TRAF3 or a mammalian ortholog thereof.

62. The method of any one of claims 3-61 , wherein in step d), a CHOP regimen or a L- CHOP regimen is selected when the subject has a mutation in TRAF3 or a mammalian ortholog thereof.

63. The method of any one of claims 59-62, wherein the mutation or the mutations in TRAF3 comprise C.1267C>T.

64. The method of any one of claims 59-62, wherein the mutation or the mutations in TRAF3 are located in a domain for trimerization of TRAF3.

65. The method of any one of claims 1-64, wherein in step c), a positive response to a CHOP regimen or a Tanovea-based regimen is predicted when (i) the subject has B-cell lymphoma (BCL) and (ii) has a mutation in TRAF3, KMT2D, or both, or mammalian orthologs thereof.

66. The method of any one of claims 3-65, wherein in step d), a CHOP regimen or a Tanovea-based regimen is selected when the subject has (i) B-cell lymphoma (BCL) and (ii) a mutation in TRAF3, KMT2D, or both, or mammalian orthologs thereof.

67. The method of any one of claims 1-66, wherein in step c), a negative response to a CHOP regimen is predicted when the subject has (i) B-cell lymphoma (BCLs) and (ii) a mutation in CCND 1 or a mammalian ortholog thereof.

68. The method of any one of claims 3-67, wherein in step d), a CHOP regimen is not selected when the subject has (i) B-cell lymphoma (BCL) and (ii) a mutation in CCND1 or a mammalian ortholog thereof.Attorney Ref: 42800-64265 / WO (OOIWO)69. The method of any one of claims 1-68, wherein in step c), a negative response to a CHOP-like regimen, a lomustine-containing regimen, or both is predicted when (i) the subject has T-cell lymphoma (TCL) and (ii) has a mutation in PIK3D, CREBBP, or both, or mammalian orthologs thereof.

70. The method of any one of claims 3-69, wherein in step d), a CHOP-like regimen, a lomustine-containing regimen, or both is not selected when (i) the subject has T-cell lymphoma (TCL) and (ii) has a mutation in PIK3D, CREBBP, or both, or mammalian orthologs thereof.

71. The method of any one of claims 1-70, wherein in step c), a positive response to a CHOP regimen is predicted when the subject has (i) T-cell lymphoma (TCL) and (ii) a mutation in KMT2C, NOTCH2 or both, or mammalian orthologs thereof.

72. The method of any one of claims 3-71 , wherein in step d), a CHOP regimen is selected when the subject has (i) T-cell lymphoma (TCL) and (ii) a mutation in KMT2C, NOTCH2 or both, or mammalian orthologs thereof.

73. The method of any one of claims 1-72, wherein in step c), a negative response to a first line therapy is predicted when the subject has a mutation in TP53, or a mammalian ortholog thereof.

74. The method of any one of claims 59-73, wherein the mutation or the mutations are somatic mutations, germline mutations, or both.

75. The method of any one of claims 1-74, wherein in step b), predicting the treatment outcome of the subject comprises: extracting features related to one or more mutations in the one or more genes; inputting the features into a machine learning model to assign the subject to one of a plurality of clusters, wherein each cluster represents a mutational profile of a plurality' of other subjects and their treatment outcome; and predicting, using the classified cluster or a random forest, the treatment outcome.

76. The method of claim 75, whereinAttorney Ref: 42800-64265 / WO (OOIWO) a. the one or more genes comprise MTOR, KLF4, VEGFA or mammalian orthologs thereof and the treatment regimen comprises doxorubicin hydrochloride; b. the one or more genes comprise MTOR, KLF4, ITK or mammalian orthologs thereof and the treatment regimen comprises doxorubicin hydrochloride; c. the one or more genes comprise CCND1, KMT2D, TP53, ARID 1 A or mammalian orthologs thereof and the treatment regimen comprises a tanovea-based regimen; d. the one or more genes comprise CCND1, TNFRSF1 1A, SLC19A1, TP53 or mammalian orthologs and the treatment regimen comprises a tanovea-based regimen; e. the one or more genes comprise CCND1, TP53 or mammalian orthologs and the treatment regimen comprises a tanovea-based regimen; f. the one or more genes comprise TP53, SETD2, SLC7A5 or mammalian orthologs and the treatment regimen comprises CCNU; g. the one or more genes comprise TP53, SETD2, SLC7A5 or mammalian orthologs and the treatment regimen comprises CCNU; h. the one or more genes comprise GNA13, TP53, ENSCAFG00000001448 or mammalian orthologs and the treatment regimen comprises CCNU; i. the one or more genes comprise EP3000, ABCC5, F0XL2 or mammalian orthologs and the treatment regimen comprises CCNU; j. the one or more genes comprise EP3000, ABCC5, F0XL2 or mammalian orthologs and the treatment regimen comprises CCNU; k. the one or more genes comprise PIK3CD, CREBBP, FBXW7, TRAF3 or mammalian orthologs and the treatment regimen comprises CHOP; or l. the one or more genes comprise N0TCH2, PIK3CD, CREBBP, KMT2C, FBXW7, TRAF3, and KMT2D or mammalian orthologs and the treatment regimen comprises CHOP.

77. The method of claim 75, wherein the machine learning model is an unsupervised model.

78. The method of claim 75 or 76, wherein the machine learning model is a K-means clustering model, a K-nearest neighbors (KNN) model, a hierarchical clustering model, or a Markov model.Attorney Ref: 42800-64265 / WO (OOIWO)79. The method of any one of claims 75-78, wherein the step of extracting features related to one or more mutations comprises: determining co-occurrence of mutations in a pair among the one or more genes; determining an odds ratio for the pair in the one or more genes; and / or providing the co-occurrence or the odds ratios as the features related to the one or more mutations.

80. The method of any one of claims 75-79, wherein the step of inputting the features into the machine learning model comprises: applying a clustering algorithm to the features that include the co-occurrence of mutations and the odds ratio to assign the subject into one of the clusters.

81. The method of any one of claims 75-80, wherein the machine learning model is a K- means clustering model, generated by the process comprising: selecting a set of candidate genes; retrieving a set of training samples, each training sample comprises mutation information in the candidate genes of training subjects and treatment outcomes of the training subjects; applying a K-means clustering algorithm to the training samples to divide the training samples into a plurality of clusters based on the mutation information in the candidate genes and the treatment outcomes; and determining a quality of the clusters based on treatment outcomes of separate clusters.

82. The method of claim 81, wherein the process further comprises: repeating the preceding steps of selecting, retrieving, applying and determining for a set of different candidate genes; and selecting a final set of genes based on the quality of the clusters corresponding to the multiple sets of candidate genes.

83. The method of claim 81 or 82, wherein the step of determining the quality of the clusters is performed based on whether and / or how well the clusters separate different treatment outcomes based on survival.Attorney Ref: 42800-64265 / WO (OOIWO)84. The method of claim 81 or 82, wherein the step of determining the quality of the clusters is performed based on a p-value between two or more clusters in predicting the treatment outcomes.

85. The method of claim 84, wherein a set of candidate genes that provides a p-value between two or more clusters larger than a threshold is not selected as the final set of genes.

86. The method of claim 81 or 82, wherein the step of determining the quality of the clusters is performed based on a hazard ratio between two or more clusters.

87. The method of any one of claims 1-74, further comprising: extracting features related to one or more mutations of the subject in a different set of one or more genes that are selected for a different treatment regimen; inputting the features into the machine learning model to assign the subject to one of a plurality of clusters, wherein each cluster represents a mutational profile of a plurality of other subjects and their treatment outcome of the different treatment regimen; predicting, using the classified cluster, the treatment outcome of the different treatment regimen; and selecting a recommended treatment regimen based on the predicted treatment outcomes.

88. The method of any one of claims 1 -74, further comprising: extracting features related to one or more mutations of the subject in a plurality set of one or more genes, wherein each set of one or more genes is selected for one of a plurality of different treatment regimens; inputting the features into the machine learning model to assign the subject to one of a plurality of clusters for each of the plurality of different treatment regimens, wherein each cluster represents a mutational profile of a plurality of other subjects and their treatment outcome of each of the plurality of different treatment regimens; predicting, using the classified cluster, the treatment outcomes for each of the plurality of different treatment regimens; and selecting a recommended treatment regimen based on the predicted treatment outcomes.Attorney Ref: 42800-64265 / WO (OOIWO)89. The method of any one of claims 1-88, wherein in step b), additional characteristics of a sample from the subject or the subject is considered for prediction of the treatment outcome.

90. The method of claim 89, wherein the additional characteristics comprise an immunophenotype of cells from the subject.

91. The method of claim 90, wherein the immunophenotype identifies the cells from the subject as B-cell lymphoma cells.

92. The method of claim 90, wherein the immunophenotype identifies the cells from the subject as T-cell lymphoma cells.

93. The method of any one of claims 90-92, wherein the immunophenotype identifies the cells from the subject by expression of one or more surface markers, optionally wherein the surface markers are selected from the group consisting of: CD21, CD20, CD3, CD4, CD8, CD5, and CD45.

94. The method of claim 93, wherein the one or more surface markers comprise cell surface receptors or cell surface ligands.

95. The method of any one of claims 89-94, wherein the additional characteristics comprises ex- vivo drug sensitivity of cells from the subject.

96. The method of claim 95, wherein the ex- vivo sensitivity of the cells of the subject is an ex-vivo sensitivity to a drug selected from the group consisting of: Actinomycin D, Docetaxel, Doxorubicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Doxycycline, Erythromycin, Itraconazole, Ketoconazole, Levofloxacin, Sparfloxacin, Tetracycline, Amitriptyline, Paroxetine, Venlafaxine, Aldosterone, Cortisol, Dexamethasone, Hydrocortisone, Methylprednisolone, Triamcinolone, Butorphanol, Loperamide, Methadone, Morphine, Pentazocine, Amiodarone, Carvedilol, Digoxin, Diltiazem, Nicardipine, Quinidine, Talinolol, Verapamil, Cyclosporine, Tacrolimus, Ivermectin, Milbemycin, Selamectin, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, and any combination thereof.Attorney Ref: 42800-64265 / WO (001WO)97. The method of any one of claims 89-96, wherein the additional characteristics of the sample or the subject comprise clinical data of the subject.

98. The method of claim 97, wherein the clinical data of the subject is selected from the group consisting of: a stage of the lymphoma, length of time since diagnosis of the lymphoma, previous treatment regimens administered to the subject, treatment outcomes of the previous treatment regimens administered to the subject, and any combination thereof.

99. The method of any one of claims 1-98, further comprising generating a physical or an electronic report about the predicted treatment outcome, a selected treatment regimen, additional characteristics of a sample from the subject or the subject, or a combination thereof.

100. The method of claim 99, wherein the physical or the electronic report is delivered to (i) the subject or (ii) the caregiver or the medical provider for the subject.

101. The method of any one of claims 1-100, wherein a sample obtained from the subject is a blood sample or a tumor sample.

102. The method of any one of claims 1-100, wherein a sample obtained from the subject comprises blood cells or tumor cells.

103. The method of any one of claims 1-102, wherein the subject is a mammal, optionally a human or a canine.

104. The method of any one of claims 1-103, wherein the subject has lymphoma selected from the group consisting of: B-cell lymphoma, T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and any combination thereof.

105. The method of any one of claims 1-103, wherein the subject has B-cell lymphoma selected from the group consisting of: small B-cell lymphoma, medium B-cell lymphoma, large B-cell lymphoma, diffuse large B-cell lymphoma, and any combination thereof.Attorney Ref: 42800-64265 / WO (001WO)106. The method of any one of claims 1-105, wherein the subject has T-cell lymphoma selected from the group consisting of: a helper-like CD4+ T cell lymphoma, a cytotoxic-like CD8+ T cell lymphoma, a CD45- T cell-zone lymphoma, an atypical T-cell lymphoma, and any combination thereof, optionally wherein the atypical T-cell lymphoma is a double negative T-cell lymphoma, a double positive T-cell lymphoma, an aberrant T-cell lymphoma, or any combination thereof.

107. A kit comprising : a) one or more probes or one or more pairs of primers, wherein the one or more probes or the one or more pairs of primers are configured to hybridize with one or more target polynucleotides in a sample, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof; and b) instructions for reacting the one or more probes or the one or more pairs of primers with the sample, thereby enriching or amplifying the one or more target polynucleotides in the sample.

108. The kit of claim 107, wherein the one or more probes or the one or more pairs of primers are configured to hybridize with one or more target polynucleotides in a sample, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

109. The kit of claim 107 or 108, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (001WO)110. The kit of claim 109, wherein the one or more probes or the one or more pairs of primers are completely complementary to wild-type sequences specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

111. The kit of claim 109, wherein the one or more probes or the one or more pairs of primers are completely complementary to sequences with one or more mutations specific to one or more genes selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

112. The kit of any one of claims 107-111, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to 21 different genes, 20 different genes, 19 different genes, 18 different genes, 17 different genes, 16 different genes, 15 different genes, 14 different genes, 13 different genes, 12 different genes, 11 different genes, 10 different genes, 9 different genes, 8 different genes, 7 different genes, 6 different genes, 5 different genes, 4 different genes, 3 different genes, 2 different genes or a single gene selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

113. The kit of any one of claims 107-111, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to at least 20 different genes, at least 19 different genes, at least 18 different genes, at least 17 different genes, at least 16 different genes, at least 15 different genes, at least 14 different genes, at least 13 different genes, at least 12 different genes, at least 11 different genes, at least 10 different genes, at least 9 different genes, at least 8 different genes, at least 7 different genes, at least 6 different genes, at least 5 different genes, at least 4 different genes, at least 3 different genes, or at least 2 different genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2,Attorney Ref: 42800-64265 / WO (001WO)CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

114. The kit of any one of claims 107-111, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to the first 20 genes, the first 19 genes, the first 18 genes, the first 17 genes, the first 16 genes, the first 15 genes, the first 14 genes, the first 13 genes, the first 12 genes, the first 11 genes, the first 10 genes, the first 9 genes, the first 8 genes, the first 7 genes, the first 6 genes, the first 5 genes, the first 4 genes, the first 3 genes, or the first 2 genes selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof.

115. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to KMT2C, KMT2D, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, and TP53, or mammalian orthologs thereof.

116. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD, NOTCH2, KMT2C, and CREBBP, or mammalian orthologs thereof.

117. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to FBXW7, TRAF3, KMT2D, and CCND1, or mammalian orthologs thereof.

118. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 and FBXW7, or mammalian orthologs thereof.

119. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 and KMT2D, or mammalian orthologs thereof.Attorney Ref: 42800-64265 / WO (001WO)120. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD and CREBBP, or mammalian orthologs thereof.

121. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to CREBBP or a mammalian ortholog thereof.

122. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to TRAF3 or a mammalian ortholog thereof.

123. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to FBXW7 or a mammalian ortholog thereof.

124. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to CCND1 or a mammalian ortholog thereof.

125. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to KMT2C and a mammalian ortholog thereof.

126. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to NOTCH2 or a mammalian ortholog thereof.

127. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to PIK3CD or a mammalian ortholog thereof.

128. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to oneAttorney Ref: 42800-64265 / WO (001WO) or more genes selected from the group consisting of: SETD2, TP53, and TRAF3 or mammalian orthologs thereof.

129. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes selected from a-d, wherein a-d are: a. KMT2C and NOTCH2, or mammalian orthologs thereof; b. KMT2D and KMT2C, or mammalian orthologs thereof; c. KMT2C and BCL1 IB, or mammalian orthologs thereof; and d. KMT2D and NOTCH2, or mammalian orthologs thereof.

130. The kit of any one of claims 107-113, wherein the one or more probes or the one or more pairs of primers are partially or completely complementary to sequences specific to one or more genes are selected from a-e, wherein a-e are: a. TRAF3 and SETD2 or mammalian orthologs thereof; b. TRAF3 and POTI, or mammalian orthologs thereof; c. TRAF3 and TBL1XR1, or mammalian orthologs thereof; d. TP53 and SETD2, or mammalian orthologs thereof; and e. POTI and FBXW7, or mammalian orthologs thereof.

131. The kit of any one of claims 107-130, wherein the one or more probes or the one or more pairs of primers comprise nucleic acid.

132. The kit of claim 131, wherein the nucleic acid is selected from the group consisting of: ribonucleic acid (RNA), deoxyribonucleic acid (DNA), 1,5-Anhydrohexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), fluoroarabino nucleic acid (FAN A), and any combination thereof.

133. The kit of any one of claims 107-132, wherein the one or more probes are on one or more panels.

134. The kit of any one of claims 107-133, wherein the one or more probes are conjugated to a biotin molecule.Attorney Ref: 42800-64265 / WO (001WO)135. The kit of any one of claim 107-134, further comprising a. a polymerase chain reaction (PCR) buffer; b. deoxynucleotide triphosphates (dNTPs); c. a polymerase; d. beads; e. universal primers; f. reaction buffer; g. a purification column; h. reagents for sequencing reaction; i. a fragmentation enzyme; and / or j. an end repair enzyme.

136. The kit of any one of claims 107-135, wherein each probe of the one or more probes comprises at least 120 nucleotides, at least 200 nucleotides at least 500 nucleotides, at least 1,000 nucleotides, at least 2,000 nucleotides, at least 3,000 nucleotides, at least 4,000 nucleotides or at least 5,000 nucleotides.

137. The kit of any one of claims 107-135, wherein each probe of the one or more probes comprises 120-7,000 nucleotides.

138. The kit of any one of claims 107-135, wherein each probe of the one or more probes comprises 200-5,000 nucleotides, 500-3,000 nucleotides, or 1,000-2,000 nucleotides.

139. The kit of any one of claims 107-136, wherein each of the one or more probes comprises an nucleotide molecule having a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence of SEQ ID NOs: 22-578, or any combination thereof.

140. The kit of any one of claims 107-139, wherein each primer of the one or more pairs of primers comprises at least 15 nucleotides, 15-40 nucleotides, or 15-30 nucleotides.

141. The kit of any one of claims 107-140, wherein the one or more pairs of primers hybridize with a sequence of a polynucleotide with a sequence identity of at least 60%, atAttorney Ref: 42800-64265 / WO (001WO) least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.

142. The kit of any one of claims 107-141, wherein each pair of the one or more pairs of primers are configured to configured to amplify a sequence of at least 50bp, at least lOObp, at least 500bp, at least lOOObp, at least 2000bp, at least 3000bp or at least 5000bp in the gene selected from KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL,. PIK3CD, FBXW7, and mammalian orthologs thereof.

143. The kit of claim 142, wherein the amplified sequence comprises a sequence corresponding to one or more exons of gene selected from KMT2C, KMT2D, BCL1 IB, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof.

144. The kit of any one of claims 107-141, wherein the one or more target polynucleotides comprise a sequence of a polynucleotide with a sequence identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, at least about 99.8%, or at least about 99.9% to a sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.Attorney Ref: 42800-64265 / WO (001WO)145. The kit of claim 144, wherein the one or more target polynucleotides comprise a polynucleotide of a sequence specific to a sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or a fragment thereof.

146. The kit of any one of claims 107-145, wherein the one or more probes or one or more pairs of primers are conjugated to a dye, optionally wherein the dye is a fluorescent dye.

147. The kit of claim 146, wherein the one or more probes or one or more pairs of primers are conjugated to a quencher.

148. The kit of any one of claims 107-147, further comprising a reagent for qPCR.

149. A method for obtaining sequence information for treatment of a subject with lymphoma, comprising: a) obtaining a sample from the subject; b) reacting the sample with one or more probes, wherein the one or more probes are configured to hybridize with one or more target polynucleotides, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, NOTCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof; c) enriching the one or more target polynucleotides in the sample; and d) obtaining sequence information of the one or more target polynucleotides.

150. The method of claim 149, wherein the one or more probes are in the kit of any of one of claims 107-148.

151. A method for obtaining sequence information for treatment of a subject with lymphoma, comprising:Attorney Ref: 42800-64265 / WO (OOIWO) a) obtaining a sample from the subject; b) reacting the sample with one or more primers, wherein the one or more primers are configured to hybridize with one or more target polynucleotides, wherein each of the one or more target polynucleotides comprises a sequence specific to a gene selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, and mammalian orthologs thereof; c) amplifying the one or more target polynucleotides in the sample; and d) obtaining sequence information of the one or more target polynucleotides.

152. The method of claim 151, wherein the one or more primers are in the kit of any of one of claims 107-145.

153. A diagnostic product of predicting a treatment outcome of a subject with lymphoma, wherein the diagnostic product is stored on a non-transitory computer readable medium and is manufactured by a process comprising: obtaining information related to a set of candidate genes; retrieving a set of training samples, each training sample comprises mutation information in the candidate genes of training subjects and treatment outcomes of the training subjects; applying a K-means clustering algorithm to the training samples to divide the training samples into a plurality of clusters based on the mutation information in the candidate genes and the treatment outcomes; and determining a quality of the clusters based on treatment outcomes of separate clusters.

154. The diagnostic product of claim 153, wherein the process further comprises: repeating the preceding steps of obtaining, retrieving, applying and determining for a set of different candidate genes; and selecting a final set of genes based on the quality of the clusters corresponding to the multiple sets of candidate genes.Attorney Ref: 42800-64265 / WO (OOIWO)155. The diagnostic product of claim 153 or 154, wherein the step of determining the quality of the clusters is performed based on separation of different outcomes by the clusters, optionally wherein the separation of different outcomes is based on survival.

156. The diagnostic product of claim 153 or 154, wherein the step of determining the quality of the clusters is performed based on a p-value between two or more separate clusters in predicting the treatment outcomes.

157. The diagnostic product of claim 156, wherein a set of candidate genes that provides a p-value between two or more clusters larger than a threshold is not selected as the final set of genes.

158. The diagnostic product of claim 153 or 154, wherein the step of determining the quality of the clusters is performed based on a hazard ratio between two or more clusters.

159. The diagnostic product of any one of claims 153-158, wherein the candidate genes are selected from the group consisting of: KMT2C, KMT2D, BCL1 IB, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1 , TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, F0XL2, PIK3CD, FBXW7, and mammalian orthologs thereof.

160. A method of predicting the treatment outcome of a test subject comprises: extracting the features related to one or more mutations of the test subject in a set of genes that are selected for a particular treatment regimen; classifying, using the diagnostic product of any one of claims 153-159, the subject into one of the plurality of clusters; and predicting, using the classified cluster, the treatment outcome of the particular treatment regimen.

161. A diagnostic product for selecting a treatment regimen for a subject with lymphoma, wherein the diagnostic product is stored on a non-transitory computer readable medium and is manufactured by a process comprising: obtaining sequence information of one or more genes in a plurality of subjects,Attorney Ref: 42800-64265 / WO (OOIWO) wherein the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PIK3CD, FBXW7, and mammalian orthologs thereof; obtaining a training dataset including a plurality of training examples, wherein each training example comprises the sequence information of an individual subject and a treatment outcome of the individual subject in response to the treatment regimen; numerically encoding the training examples in the training dataset, comprising numerically encoding the sequence information of the individual subject or mutation information identified from the sequence information, and numerically encoding the treatment outcome of the individual subject in response to the treatment regimen; for a diagnostic model comprising a machine learning model that has a plurality of layers, each layer having a plurality of parameters, the layers comprising an input layer for receiving the numerically encoded sequence information or mutation information and an output layer indicating a treatment outcome in response to the treatment regimen, for one or more iterations of the training process:(a) for a set of training examples for the current iteration, applying parameters of the machine learning model to generate estimated likelihoods for the set of training examples,(b) computing a loss function indicating a difference between the estimated likelihoods and the numerically encoded treatment outcome for the set of training examples for the current iteration,(c) repeatedly backpropagating one or more error terms obtained from the loss function, to update the parameters of the layers of the diagnostic model, and(d) stopping the backpropagation after the loss function satisfies a criterion; and storing the updated set of parameters for the layers of the diagnostic model on the computer readable storage medium.Attorney Ref: 42800-64265 / WO (OOIWO)162. A method of treating a test subject with lymphoma, comprising: obtaining sequence information of one or more genes in the test subject, wherein the one or more genes are selected from the group consisting of: KMT2C, KMT2D, BCL11B, N0TCH2, TRAF3, CCND1, ARID1A, CREBBP, TP53, SPEF2, CCND3, POTI, SETD2, RFC1, TNFRSF11A, ABCC4, ATM, BRCA1, MYC, VEGFA, ABL1, MTOR, KLF4, VEGFA, ITK, SLC19A1, SLC7A5, GNA13, ENSCAFG00000001448, ABCC5, FOXL2, PTK3CD, FBXW7, and mammalian orthologs thereof; applying the sequence information or mutation information obtained from the sequence information to the diagnostic product of claim 161, thereby predicting a treatment outcome of the test subject, and providing information related to the prediction to (i) the test subject or (ii) a care giver or a medical provider for the test subject for use in treatment of the test subject.

163. The method of claim 162, further comprising generating a physical or electronic report related to the prediction.

164. The method of claim 162 or 163, further comprising selecting a treatment regimen based on the prediction.

165. The method of any one of claims 162-164, further comprising treating the test subject by the selected treatment regimen.

Images