Methods and vaccine compositions for the treatment of cancer

Abstract

In the present invention, the inventors reveal that noncoding RNA, a known source of noncanonical peptides (also called dark matter) and tumour-specific antigens, can shape the precancer immune contexture and are associated with polyp and cancer risk. Through the multimodal characterisation of a unique dataset of 135 well-annotated cancer and precancer lesions from patients developing polyps at low and high frequency, the inventors identified high expression of noncoding RNAs, as a major differentiator of polyp development rate. Noncoding RNAs were also associated with increased immunogenicity associated with increased mature tertiary lymphoid structures within the microenvironment of pre-cancer lesion, higher quantity and quality of adaptive immune cells, including B- and T-cells. Thus, the inventors propose that early carcinogenesis is shaped by noncoding RNA expression and immune microenvironment. These compelling findings reveal potential targets for immune modulation approaches in individuals at high risk of developing colorectal cancer. More particularly, the inventors identified dark antigens (i.e. peptides) that can be used in vaccines for the treatment of cancer, in particular, the prophylactic treatment of cancer.

Description

[0001] METHODS AND VACCINE COMPOSITIONS FOR THE TREATMENT OF CANCER

[0002] FIELD OF THE INVENTION:

[0003] The present invention is in the field of medicine, in particular oncology and immunology.

[0004] BACKGROUND OF THE INVENTION:

[0005] Early detection and cancer prevention could strongly reduce cancer incidence and mortality1. Most solid cancers develop from benign lesions, called polyps in colorectal carcinoma (CRC). Understanding the mechanisms of early colorectal carcinogenesis and the underlying role of the microenvironment in polyps can pave the way for personalised treatment and cancer prevention6.

[0006] Among the factors shaping carcinogenesis, the immune system present in the tumour microenvironment (TME) has been shown to be associated with the clinical outcome of cancer patients in terms of both survival and therapeutic responses2,7. The presence of tumour-specific antigens (TSA) is believed to be critical for eliciting a proper immune response. In particular, aberrant expression of noncoding portions of the genome, called ncRNA, have been shown to be a major source of immunogenic TSA8'10.

[0007] As cancers are usually detected and surgically removed at advanced stages, immune TME in precancerous lesions is understudied compared to invasive stages. Recently, studies in various types of cancer7,11'13, including CRC14'16, demonstrated that the immune system is capable of recognising and eliminating tumour cells even at the early stages of carcinogenesis, and that mechanisms leading to immune escape can be observed in premalignant states11,12.

[0008] Most CRC develop from two premalignant pathways associated with specific polyps and mutation sequences, the serrated and the adenomatous pathways15,17'19. In addition, several risk factors such as hereditary syndromes or inflammatory bowel disease, have been associated with a high rate of polyp development18. However, among individuals developing sporadic polyps, some patients will still develop an abnormally high number of polyps, which have been repetitively associated with increased risk of CRC20'22. Characterization of the immune TME in these patients could lead to a better understanding of the mechanisms associated with this high rate of polyp development and improve patient stratification and follow-up. Until now, the rarity of preinvasive lesion cohorts with various polyp development rates has restricted our knowledge of their molecular and immune profiles14'16,23.

[0009] SUMMARY OF THE INVENTION:

[0010] The present invention is defined by the claims. In particular, the present invention relates to methods of detecting, predicting and preventing colorectal cancer with a prophylactic treatment in subjects having premalignant lesions.

[0011] SUMMARY OF THE INVENTION:

[0012] The present invention is defined by the claims. In particular, the present invention relates to methods and vaccine compositions for the treatment of cancer. More particularly, the inventors identified dark antigens (i.e. peptides) that can be used in vaccines for the treatment of cancer.

[0013] DETAILED DESCRIPTION OF THE INVENTION:

[0014] The improvement of cancer outcome will ultimately depend on early precancer detection and prophylactic treatment1. Tumour-specific antigens and immune contexture have been shown to play a pivotal role in tumour progression2,3, but little is known about factors shaping precancerous phases. In colorectal carcinoma, the highest adaptive immune response has been found at the earliest stage of invasive carcinoma4,5, suggesting an early function of the immune system. Understanding and deciphering molecular processes and immune dynamics in premalignant lesions has the potential to reveal important mechanisms associated with early carcinogenesis. Herein, the inventors reveal that noncoding RNA, a known source of noncanonical peptides (also called dark matter) and tumour-specific antigens, can shape the precancer immune contexture and are associated with polyp and cancer risk. Through the multimodal characterisation of a unique dataset of 135 well-annotated cancer and precancer lesions from patients developing polyps at low and high frequency, the inventors identified high expression of noncoding RNAs, as a major differentiator of polyp development rate. Noncoding RNAs were also associated with increased immunogenicity associated with increased mature tertiary lymphoid structures within the microenvironment of pre-cancer lesion, higher quantity and quality of adaptive immune cells, including B- and T-cells. Thus, inventors’ work unveils that dark matter plays an important role in mounting a proper immune response during colorectal carcinogenesis, favouring prevention of precancer or cancer development. The inventors propose that early carcinogenesis is shaped by noncoding RNA expression and immune microenvironment. These compelling findings reveal potential early targets for prophylactic immune modulation approaches in individuals having cancer or at high risk of developing cancer.

[0015] The present invention relates to a method for the treatment of a cancer in a subject comprising administering to the subject a therapeutically effective amount of i) one or more dark antigen(s) and / or ii) one polynucleotide encoding for one or more dark antigen(s).

[0016] As used herein, the term “subject” is interchangeable with the term “individual” or “patient”, and may refer to a subj ect to be treated by the methods disclosed herein. In particular, the patient is affected or likely to suffer from a cancer, more particularly a skin cancer. In some embodiments, the patient is a mammal. Non-limiting examples of mammals include rodents (e.g., mice and rats), primates (e.g., lemurs, bushbabies, monkeys, apes, and humans), rabbits, dogs (e.g., companion dogs, service dogs, or work dogs such as police dogs, military dogs, race dogs, or show dogs), horses (such as race horses and work horses), cats (e.g., domesticated cats), livestock (such as pigs, bovines, donkeys, mules, bison, goats, camels, and sheep), and deer. In some embodiments, the mammal is a human. In some embodiments, the patient is a human infant. In some embodiments, the patient is a human child. In some embodiments, the patient is a human adult.

[0017] In some embodiments, the method of the present invention is particularly suitable for the treatment of a cancer selected from the group consisting of adrenal cortical cancer, anal cancer, bile duct cancer (e.g. periphilar cancer, distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g. osteoblastoma, osteochrondroma, hemangioma, chondromyxoid fibroma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, giant cell tumor of the bone, chordoma), brain and central nervous system cancer (e.g. meningioma, astocytoma, oligodendrogliomas, ependymoma, gliomas, medulloblastoma, ganglioglioma, Schwannoma, germinoma, craniopharyngioma), breast cancer (e.g. ductal carcinoma in situ, infiltrating ductal carcinoma, infiltrating lobular carcinoma, lobular carcinoma in situ, gynecomastia), Castleman disease (e.g. giant lymph node hyperplasia, angiofollicular lymph node hyperplasia), cervical cancer, colorectal cancer, endometrial cancer (e.g. endometrial adenocarcinoma, adenocanthoma, papillary serous adnocarcinoma, clear cell), esophagus cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g. choriocarcinoma, chorioadenoma destruens), Hodgkin's disease, Kaposi's sarcoma, kidney cancer (e.g. renal cell cancer), laryngeal and hypopharyngeal cancer, liver cancer (e.g. hemangioma, hepatic adenoma, focal nodular hyperplasia, hepatocellular carcinoma), lung cancer (e.g. small cell lung cancer, non-small cell lung cancer, squamous lung cancer), mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer (e.g. esthesioneuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g. embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, skin cancer (e.g. melanoma, nonmelanoma skin cancer), stomach cancer, testicular cancer (e.g. seminoma, nonseminoma germ cell cancer), thymus cancer, thyroid cancer (e.g. follicular carcinoma, anaplastic carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma,), vaginal cancer, vulvar cancer, and uterine cancer (e.g. uterine leiomyosarcoma).

[0018] In some embodiments, the method of the present invention is particularly suitable for treatment of colorectal cancer.

[0019] As used herein, the term “colorectal cancer” includes the well-accepted medical definition that defines colorectal cancer as a medical condition characterized by cancer of cells of the intestinal tract below the small intestine (i.e., the large intestine (colon), including the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum). Additionally, as used herein, the term “colorectal cancer” also further includes medical conditions, which are characterized by cancer of cells of the duodenum and small intestine (jejunum and ileum).

[0020] As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).

[0021] In particular, the method of the present invention is particularly suitable for the preventing the progression of cancer. As used herein, the term “progression” means increasing in scope or severity, advancing, growing or becoming worse.

[0022] In particular, the method of the present invention is particularly suitable for preventing the recurrence of cancer. As used herein, the term “recurrence” means the return of a disease after a remission.

[0023] In particular, the method of the present invention is particularly suitable for preventing metastases. As used herein, the term “metastasis” refers to the transfer of a disease from one organ or part thereof to another not directly connected with it. Metastasis can occur for example as a result of transfer of malignant cells from one organ (for example breast) to other organs.

[0024] In particular, the method of the present invention is particularly suitable for the prophylactic treatment of cancer.

[0025] As used herein, the terms "prophylaxis" or "prophylactic use" and "prophylactic treatment" as used herein, refer to any medical or public health procedure whose purpose is to prevent a disease. As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a subject with the disease.

[0026] More particularly, the method of the present invention is particularly suitable for the prophylactic treatment of a subject who has at least one premalignant lesion.

[0027] As used herein, the term “premalignant lesion” means tissue that is not yet malignant, but may be capable of becoming malignant. As used herein, the terms “lesion” refer to an area of a tissue that has, or appears to have, undergone a pathological change. For example, a premalignant lesion may be histologically identified as metaplastic, hyperplastic, dysplastic or an in situ carcinoma. In some embodiments, the premalignant lesion is a low or high grade dysplasia. Dysplasia is defined as an unequivocal neoplastic alteration of the epithelium. Dysplasia can itself be subdivided objectively into high grade and low grade depending on the proportion of dysplastic cells in the epithelium. In low grade dysplastic cells are largely confined to the basal layers of the epithelium, whereas in high grade dysplasia they regularly reach the upper part of the epithelium.

[0028] In some embodiments, the subject has at least one polyp. As used herein, the term "polyp" refers to an abnormal biological mass that is projecting from a mucous membrane. Polyps may be found in a number of tissues, including but not limited to colon, stomach, nose, ear, sinus(es), urinary bladder, and uterus.

[0029] In some embodiments, the subject for which the prophylaxis of cancer would be suitable follows a surveillance program. As used herein, the term “surveillance program” refers to a set of examinations or procedures used to longitudinally follow up individuals identified in a screening program to have premalignant lesions. A “surveillance program” includes strategies for both surveillance interval and surveillance intensity. For instance, examination may be performed by one or more suitable procedures, e.g., endoscopy (e.g. colonoscopy), sample occult blood testing, computed tomography (CT) or other imaging procedure.

[0030] As used herein, the term “dark antigen” has its general meaning in the art and refers to a class of cancer-specific HLA-restricted epitope derived from aberrant epigenetic activity in the genomic “dark matter” of the tumor cell, leading to translation of polypeptides from previously thought to be non-coding genomic regions. Dark Antigens represent a vast untapped resource of novel, shared, homogenously expressed cancer-specific targets from a broad range of solid tumor types. Typically dark antigens are encoded by non-coding RNAs (ncRNAs).

[0031] As used herein, the term “non-coding RNA” or “ncRNA” has its general meaning in the art and is commonly employed for RNA that does not encode a protein, but this does not mean that such RNAs do not contain information nor have function. Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is in fact transcribed into ncRNAs, many of which are alternatively spliced and / or processed into smaller products. Abundant and functionally important types of non-coding RNAs include transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as small RNAs such as microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs and the long ncRNAs such as Xist and HOTAIR. In some embodiments, the non-coding RNA of the present invention is a “long noncoding RNA” (or “IncRNA”), i.e. a ncRNA having more than 200 nucleotides. In the present specification, the name of each of the various ncRNAs of interest refers to the internationally recognised name of the corresponding gene, as found in internationally recognised gene sequences and protein sequences databases, including in the database from the Ensembl database that is available notably at the following internet address: http: / / www.ensembl.org. Through these internationally recognized sequence databases, the nucleic acid and the amino acid sequences corresponding to each of the ncRNA of interest described herein may be retrieved by the one skilled in the art.

[0032] As used herein, the term “epitope” has its general meaning in the art and a fragment of at least 8 amino acids that is recognized by an immune response component. As used herein, the term “immune response component” include, but is not limited to, at least a part of a macrophage, a lymphocyte, a T-lymphocyte, a killer T-lymphocyte, an immune response modulator, a helper T-lymphocyte, an antigen receptor, an antigen presenting cell, a cytotoxic T-lymphocyte, a T-8 lymphocyte, a CD1 molecule, a B lymphocyte, an antibody, a recombinant antibody, a genetically engineered antibody, a chimeric antibody, a monospecific antibody, a bispecific antibody, a multispecific antibody, a diabody, a chimeric antibody, a humanized antibody, a human antibody, a heteroantibody, a monoclonal antibody, a polyclonal antibody, an antibody fragment, and / or synthetic antibody. The term “epitope” may be used interchangeably with antigen, paratope binding site, antigenic determinant, and / or determinant.

[0033] As used herein, the term “human leukocyte antigen system” or “HLA” has its general meaning in the art and refers to the major histocompatibility complex (MHC) in humans. The locus contains many genes that encode cell-surface antigen-presenting proteins. The proteins encoded by certain genes are also known as antigens. The major HLA antigens are HLA class I antigens (A, B and C) and HLA class II antigens (DR, DP and DQ). HLA class I antigens present peptides (8-12 amino acids) usually originating from inside the cell, and attract CD8 cytotoxic T cells that destroy cells. HLA class II antigens present peptides usually originating from outside cells to CD4 T-helper-lymphocytes, which stimulate B-cells and other immune cells.

[0034] In some embodiments, the dark antigen is encoded by one ncRNA selected from Table A.

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050] In some embodiments, the dark antigen is a HLA class I restricted epitope.

[0051] In some embodiments, the dark antigen is a HLA-A*0101 restricted epitope. In some embodiments, the HLA-A*0101 restricted epitope is selected from Table 1.

[0052] Table 1:

[0053]

[0054]

[0055] In some embodiments, the dark antigen is a HLA-A*0201 restricted epitope. In some embodiments, the HLA-A*0201 restricted epitope is selected from Table 2.

[0056] Table 2:

[0057]

[0058]

[0059] In some embodiments, the dark antigen is a HLA-A*02:06 restricted epitope. In some embodiments, the HLA-A*02:06 restricted epitope is selected from Table 3.

[0060] Table 3:

[0061]

[0062] In some embodiments, the dark antigen is a HLA-A*03:01 restricted epitope. In some embodiments, the HLA-A*03:01 restricted epitope is selected from Table 4.

[0063] Table 4:

[0064]

[0065]

[0066] In some embodiments, the dark antigen is a HLA-A* 11:01 restricted epitope. In some embodiments, the HLA-A* 11:01 restricted epitope is selected from Table 5.

[0067] Table 5:

[0068]

[0069]

[0070] In some embodiments, the dark antigen is a HLA-A*23:01 restricted epitope. In some embodiments, the HLA-A*23:01 restricted epitope is selected from Table 6.

[0071] Table 6:

[0072]

[0073] In some embodiments, the dark antigen is a HLA-A*24:02 restricted epitope. In some embodiments, the HLA-A* 14:02 restricted epitope is selected from Table 7.

[0074] Table 7:

[0075]

[0076] In some embodiments, the dark antigen is a HLA-A*26:01 restricted epitope. In some embodiments, the HLA-A*26:01 restricted epitope is selected from Table 8.

[0077] Table 8:

[0078]

[0079]

[0080] In some embodiments, the dark antigen is a HLA-A*30:01 restricted epitope. In some embodiments, the HLA-A*30:01 restricted epitope is selected from Table 9.

[0081] Table 9:

[0082]

[0083] In some embodiments, the dark antigen is a HLA-A*32:01 restricted epitope. In some embodiments, the HLA-A*32:01 restricted epitope is selected from Table 10.

[0084] Table 10:

[0085]

[0086] In some embodiments, the dark antigen is a HLA-A*68:02 restricted epitope. In some embodiments, the HLA-A*68:02 restricted epitope is selected from Table 11:

[0087] Table 11:

[0088]

[0089]

[0090] In some embodiments, the dark antigen is a HLA-B*08:01 restricted epitope. In some embodiments, the HLA-B*08:01 restricted epitope is selected from Table 12.

[0091] Table 12:

[0092]

[0093]

[0094] In some embodiments, the dark antigen is a HLA-B* 13:02 restricted epitope. In some embodiments, the HLA-B* 13:02 restricted epitope is selected from Table 13.

[0095] Table 13:

[0096]

[0097] In some embodiments, the dark antigen is a HLA-B* 14:01 restricted epitope. In some embodiments, the HLA-B* 14:01 restricted epitope is selected from Table 14.

[0098] Table 14:

[0099]

[0100] In some embodiments, the dark antigen is a HLA-B*15:01 restricted epitope. In some embodiments, the HLA-B*15:01 restricted epitope is selected from Table 15.

[0101] Table 15:

[0102]

[0103]

[0104] In some embodiments, the dark antigen is a HLA-B*18:01 restricted epitope. In some embodiments, the HLA-B*18:01 restricted epitope is selected from Table 16.

[0105] Table 16:

[0106]

[0107] In some embodiments, the dark antigen is a HLA-B*27:05 restricted epitope. In some embodiments, the HLA-B*27:05 restricted epitope is selected from Table 17.

[0108] Table 17:

[0109]

[0110] In some embodiments, the dark antigen is a HLA-B*35:01 restricted epitope. In some embodiments, the HLA-B*35:01 restricted epitope is selected from Table 18.

[0111] Table 18:

[0112]

[0113]

[0114] In some embodiments, the dark antigen is a HLA-B*35:03 restricted epitope. In some embodiments, the HLA-B*35:03 restricted epitope is selected from Table 19.

[0115] Table 19:

[0116]

[0117]

[0118] In some embodiments, the dark antigen is a HLA-B*35:08 restricted epitope. In some embodiments, the HLA-B*35:08 restricted epitope is selected from Table 20.

[0119] Table 20:

[0120]

[0121] In some embodiments, the dark antigen is a HLA-B*37:01 restricted epitope. In some embodiments, the HLA-B*37:01 restricted epitope is selected from Table 21.

[0122] Table 21:

[0123]

[0124]

[0125] In some embodiments, the dark antigen is a HLA-B*38:01 restricted epitope. In some embodiments, the HLA-B*38:01 restricted epitope is selected from Table 22.

[0126] Table 22:

[0127]

[0128]

[0129] In some embodiments, the dark antigen is a HLA-B*40:01 restricted epitope. In some embodiments, the HLA-B*40:01 restricted epitope is selected from Table 23.

[0130] Table 23:

[0131]

[0132] In some embodiments, the dark antigen is a HLA-B*44:02 restricted epitope. In some embodiments, the HLA-B*44:02 restricted epitope is selected from Table 24.

[0133] Table 24:

[0134]

[0135] In some embodiments, the dark antigen is a HLA-B*51:01 restricted epitope. In some embodiments, the HLA-B*51:01 restricted epitope is selected from Table 25.

[0136] Table 25:

[0137]

[0138]

[0139] In some embodiments, the dark antigen is a HLA-B*56:01 restricted epitope. In some embodiments, the HLA-B*56:01 restricted epitope is selected from Table 26.

[0140] Table 26:

[0141]

[0142]

[0143] In some embodiments, the dark antigen is a HLA-B*57:01 restricted epitope. In some embodiments, the HLA-B*57:01 restricted epitope is selected from Table 27.

[0144] Table 27:

[0145]

[0146] In some embodiments, the dark antigen is a HLA-B*57:03 restricted epitope. In some embodiments, the HLA-B*57:03 restricted epitope is selected from Table 28.

[0147] Table 28:

[0148]

[0149]

[0150] In some embodiments, the dark antigen is a HLA-B*58:01 restricted epitope. In some embodiments, the HLA-B*58:01 restricted epitope is selected from Table 29.

[0151] Table 29:

[0152]

[0153]

[0154] In some embodiments, the dark antigen is a HLA-C*01:02 restricted epitope. In some embodiments, the HLA-C*01:02 restricted epitope is selected from Table 30.

[0155] Table 30:

[0156]

[0157] In some embodiments, the dark antigen is a HLA-C*02:02 restricted epitope. In some embodiments, the HLA-C*02:02 restricted epitope is selected from Table 31.

[0158] Table 31:

[0159]

[0160] In some embodiments, the dark antigen is a HLA-C*03:03 restricted epitope. In some embodiments, the HLA-C*03:03 restricted epitope is selected from Table 32.

[0161] Table 32:

[0162]

[0163]

[0164] In some embodiments, the dark antigen is a HLA-C*03:04 restricted epitope. In some embodiments, the HLA-C*03:04 restricted epitope is selected from Table 33.

[0165] Table 33:

[0166]

[0167]

[0168] In some embodiments, the dark antigen is a HLA-C*04:01 restricted epitope. In some embodiments, the HLA-C*04:01 restricted epitope is selected from Table 34.

[0169] Table 34:

[0170]

[0171] In some embodiments, the dark antigen is a HLA-C*05:01 restricted epitope. In some embodiments, the HLA-C*05:01 restricted epitope is selected from Table 35.

[0172] Table 35:

[0173]

[0174]

[0175] In some embodiments, the dark antigen is a HLA-C*06:02 restricted epitope. In some embodiments, the HLA-C*06:02 restricted epitope is selected from Table 36.

[0176] Table 36:

[0177]

[0178]

[0179] In some embodiments, the dark antigen is a HLA-C*07:01 restricted epitope. In some embodiments, the HLA-C*07:01 restricted epitope is selected from Table 37.

[0180] Table 37:

[0181]

[0182] In some embodiments, the dark antigen is a HLA-C*07:02 restricted epitope. In some embodiments, the HLA-C*07:02 restricted epitope is selected from Table 38.

[0183] Table 38:

[0184]

[0185] In some embodiments, the dark antigen is a HLA-C*08:02 restricted epitope. In some embodiments, the HLA-C*08:02 restricted epitope is selected from Table 39.

[0186] Table 39:

[0187]

[0188]

[0189] In some embodiments, the dark antigen is a HLA-C* 12:03 restricted epitope. In some embodiments, the HLA-C* 12:03 restricted epitope is selected from Table 40.

[0190] Table 40:

[0191]

[0192]

[0193] In some embodiments, the dark antigen is a HLA-C* 15:02 restricted epitope. In some embodiments, the HLA-C* 15:02 restricted epitope is selected from Table 41.

[0194] Table 41:

[0195]

[0196] In some embodiments, the dark antigen is a HLA-C* 15:04 restricted epitope. In some embodiments, the HLA-C* 15:04 restricted epitope is selected from Table 42.

[0197] Table 42:

[0198]

[0199]

[0200] In some embodiments, the subject is administered with a plurality of HLA-restricted epitopes (i.e. a “cocktail” of HLA-restricted epitopes). It is particularly advantageous that the HLA-restricted epitopes in the cocktail are capable of being bound by MHC molecules of more than one HLA allele. For example, in some embodiments, the cocktail comprises a first HLA-restricted epitope that is capable of being bound by MHC molecules of allele HLA-A*0201 and a second HLA-restricted epitope that is capable of being bound by MHC molecules of allele HLA-A-A*03. It is also to be understood that in some embodiments the cocktail comprises more than two HLA-restricted epitopes having different sequences (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or HLA-restricted epitopes). In some embodiments, the cocktail comprises 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; 294; 295; 296; 297; 298; 299; 300; 301; 302; 303; 304; 305; 306; 307; 308; 309; 310; 311; 312; 313; 314; 315; 316; 317; 318; 319; 320; 321; 322; 323; 324; 325; 326; 327; 328; 329; 330; 331; 332; 333; 334; 335; 336; 337; 338; 339; 340; 341; 342; 343; 344; 345; 346; 347; 348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 358; 359; 360; 361; 362; 363; 364; 365; 366; 367; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377, or more HLA-restricted epitopes encoded by the ncRNAs selected from Table A or selected from Tables 1-41.

[0201] In some embodiments, the dark antigen is one or more ncRNAs as disclosed in any one of Tables 44 to 67 below (without considering in these Tables those only referring to protein coding markers).

[0202] In some embodiments, the dark antigen is fused to a heterologous polypeptide to form a fusion protein. As used herein, a “fusion protein" comprises all or part (typically biologically active) of a dark antigen operably linked to a heterologous polypeptide (i.e., a polypeptide which does not derive from the same protein). Within the fusion protein, the term "operably linked" is intended to indicate that the dark antigen and the heterologous polypeptide are fused in-frame to each other. The heterologous polypeptide can be fused to the N-terminus or C-terminus of the dark antigen. In some embodiments, the dark antigen is fused either directly or via a linker to the heterologous polypeptide. As used herein, the term "directly" means that the (first or last) amino acid at the terminal end (N or C-terminal end) of the dark antigen is fused to the (first or last) amino acid at the terminal end (N or C-terminal end) of heterologous polypeptide. This direct fusion can occur naturally as described in (Vigneron et al., Science 2004, PMID 15001714), (Warren et al., Science 2006, PMID 16960008), (Berkers et al., J. Immunol. 2015a, PMID 26401000), (Berkers et al., J. Immunol. 2015b, PMID 26401003), (Delong et al., Science 2016, PMID 26912858) (Liepe et al., Science 2016, PMID 27846572), (Babon et al., Nat. Med.

[0203] 2016, PMID 27798614). In this case, a sequence stretch shorter than 8 amino acid of the dark antigen can be fused with a heterologous peptide. As used herein, the term "linker" refers to a sequence of at least one amino acid that links the dark antigen with the heterologous polypeptide. Linkers are well known to one of ordinary skill in the art and typically comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more amino acids.

[0204] In some embodiments, the fusion protein of the present invention comprises an amino acid sequence consisting of a portion of an Fc region fused to the amino acid sequence of the dark antigen. As used herein, the term “Fc region” includes amino acid sequences derived from the constant region of an antibody heavy chain. The Fc region is the portion of a heavy chain constant region of an antibody beginning at the N-terminal of the hinge region at the papain cleavage site, at about position 216 according to the EU index and including the hinge, CH2, and CH3 domains. Exemplary Fc regions or portions thereof that may be used in the practice of the invention are well known in the art. In some embodiments, the Fc region is the Fc region of an IgG antibody, preferably of an IgGl or IgG4 antibody. In some embodiments, the Fc region of the fusion protein includes substantially the entire Fc region of an antibody, beginning in the hinge region just upstream of the papain cleavage site which defines IgG Fc chemically (about residue 216 EU numbering, taking the first residue of heavy chain constant region to be 114) and ending at its C-terminus. The precise site at which the fusion is made is not critical; particular sites are well known and may be selected in order to optimize the biological activity, secretion, or binding characteristics of the molecule. Methods for making fusion proteins are known in the art.

[0205] In some embodiments, the dark antigen is fused or conjugated to an antibody for forming an “immunoconjugate”.

[0206] As used herein, the term "antibody" is thus used to refer to any antibody -like molecule that has an antigen binding region, and this term includes antibody fragments that comprise an antigen binding domain such as Fab', Fab, F(ab')2, single domain antibodies (DABs or VHH), TandAbs dimer, Fv, scFv (single chain Fv), dsFv, ds-scFv, Fd, linear antibodies, minibodies, diabodies, bispecific antibody fragments, bibody, tribody (scFv-Fab fusions, bispecific or trispecific, respectively); sc-diabody; kappa(lambda) bodies (scFv-CL fusions); DVD-Ig (dual variable domain antibody, bispecific format); SIP (small immunoprotein, a kind of minibody); SMIP ("small modular immunopharmaceutical" scFv-Fc dimer; DART (ds-stabilized diabody "Dual Affinity ReTargeting"); small antibody mimetics comprising one or more CDRs and the like. In some embodiments, the antibody is a chimeric antibody, a humanized antibody or a human antibody. The techniques for preparing and using various antibody-based constructs and fragments are well known in the art. Significantly, as is well-known in the art, only a small portion of an antibody molecule, the paratope, is involved in the binding of the antibody to its epitope (see, in general, Clark, W. R. (1986) The Experimental Foundations of Modern Immunology Wiley & Sons, Inc., New York; Roitt, I. (1991) Essential Immunology, 7th Ed., Blackwell Scientific Publications, Oxford). The Fc' and Fc regions, for example, are effectors of the complement cascade but are not involved in antigen binding. An antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region, designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody. Similarly, an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region, designated a Fab fragment, retains one of the antigen binding sites of an intact antibody molecule. Proceeding further, Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd. The Fd fragments are the major determinants of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation. Thus, as will be apparent to one of ordinary skill in the art, the present invention also provides for F(ab') 2 Fab, Fv and Fd fragments. Antibodies can be indeed fragmented using conventional techniques. For example, F(ab')2 fragments can be generated by treating the antibody with pepsin. The resulting F(ab')2 fragment can be treated to reduce disulfide bridges to produce Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, Fv, dsFv, Fd, dAbs, TandAbs, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant techniques or can be chemically synthesized. Techniques for producing antibody fragments are well known and described in the art. For example, each of Beckman et al., 2006; Holliger & Hudson, 2005; Le Gall et al., 2004; Reff & Heard, 2001; Reiter et al., 1996; and Young et al., 1995 further describe and enable the production of effective antibody fragments. The various antibody molecules and fragments may derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4. The present invention also includes so-called single chain antibodies. The term “single domain antibody” (sdAb) or "VHH" refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such VHH are also called “nanobody®”. According to the invention, sdAb can particularly be llama sdAb. Typically, the antibody is directed against a surface antigen of an antigen presenting cell so that the dark antigen is targeted to said cell to elicit an immune response (e.g. tolerance). As used herein the term “APCs” or "Antigen Presenting Cells" (APC) are cells that are capable of activating T-cells, and include, but are not limited to, certain macrophages, B cells and DCs. In some embodiments, the antibody is directed against a surface antigen of a DC. "Dendritic cells" (DCs) refer to any member of a diverse population of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their distinctive morphology, high levels of surface MHC-class II expression (Steinman, et al., Ann. Rev. Immunol. 9:271 (1991); incorporated herein by reference for its description of such cells). These cells can be isolated from a number of tissue sources, and conveniently, from peripheral blood, as described herein. Accordingly, the antibody is selected from an antibody that specifically binds to DC immunoreceptor (DCIR), MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD1 lb, CD14, CD15, CD16, CD19, CD20, CD29, CD31, CD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, Langerin, DECTIN-1, B7-1, B7-2, IFN-y receptor and IL-2 receptor, ICAM-1, Fey receptor, LOX-1, and ASPGR. In some embodiments, the antibody is specific for a cell surface marker of a professional APC. Preferably, the antibody is specific for a cell surface marker of a DC, for example, CD83, CMRF-44 or CMRF-56. The antibody may be specific for a cell surface marker of another professional APC, such as a B cell or a macrophage. CD40 is expressed on both dendritic cells, B cells, and other APCs so that a larger number of APCs would be recruited.

[0207] The HLA-restricted epitopes of the present invention may be prepared by any technique known to those of skill in the art, including the expression of proteins, polypeptides or peptides through standard molecular biological techniques, the isolation of proteins or peptides from natural sources, in vitro translation, or the chemical synthesis of proteins or peptides. The nucleotide and protein, polypeptide and peptide sequences corresponding to various genes have been previously disclosed, and may be found at computerized databases known to those of ordinary skill in the art. One such database is the National Center for Biotechnology Information’s Genbank and GenPept databases located at the National Institutes of Health website. The coding regions for known genes may be amplified and / or expressed using the techniques disclosed herein or as would be known to those of ordinary skill in the art. Alternatively, various commercial preparations of proteins, polypeptides and peptides are known to those of skill in the art. In particular, peptides can be readily synthesized chemically utilizing reagents that are free of contaminating bacterial or animal substances (Merrifield RB: Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. J. Am. Chem. Soc.85:2149-54, 1963). In some embodiments, HLA-restricted epitopes are prepared by (1) parallel solid-phase synthesis on multi-channel instruments using uniform synthesis and cleavage conditions; (2) purification over a RP-HPLC column with column stripping; and re-washing, but not replacement, between peptides; followed by (3) analysis with a limited set of the most informative assays. The Good Manufacturing Practices (GMP) footprint can be defined around the set of peptides for an individual patient, thus requiring suite changeover procedures only between syntheses of peptides for different patients. Alternatively, a nucleic acid (e.g., a polynucleotide) encoding a HLA-restricted epitope of the invention may be used to produce the HLA-restricted epitope in vitro. The polynucleotide may be, e.g., DNA, cDNA, PNA, CNA, RNA, either single- and / or double-stranded, or native or stabilized forms of polynucleotides, such as e.g. polynucleotides with a phosphorothiate backbone, or combinations thereof and it may or may not contain introns so long as it codes for the peptide. In some embodiments in vitro translation is used to produce the peptide. Many exemplary systems exist that one skilled in the art could utilize (e.g., Retie Lysate IVT Kit, Life Technologies, Waltham, MA). An expression vector capable of expressing a polypeptide can also be prepared. Expression vectors for different cell types are well known in the art and can be selected without undue experimentation. Generally, the DNA is inserted into an expression vector, such as a plasmid, in proper orientation and correct reading frame for expression. If necessary, the DNA may be linked to the appropriate transcriptional and translational regulatory control nucleotide sequences recognized by the desired host (e.g., bacteria), although such controls are generally available in the expression vector. The vector is then introduced into the host bacteria for cloning using standard techniques (see, e.g., Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N. Y.). Expression vectors comprising the isolated polynucleotides, as well as host cells containing the expression vectors, are also contemplated.

[0208] In some embodiments, the HLA-restricted epitope(s) is / are administered to the patient in the form of one or more polynucleotides encoding the desired HLA-restricted epitopes. In some embodiments, one or more HLA-restricted epitopes of the invention may be encoded by a single polynucleotide. In some embodiments, the patient is administered with a plurality of polynucleotides that encodes a plurality of HLA-restricted epitopes. In some embodiments, the patient is administered with a plurality of polynucleotides that encodes a plurality of HLA-restricted epitopes. It is particularly advantageous that the HLA-restricted are capable of being bound by MHC molecules of more than one HLA allele. In some embodiments the plurality of polynucleotides encode more than two HLA-restricted epitopes having different sequences (e.g.

[0209] 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or HLA-restricted epitopes). In some embodiments, the plurality of polynucleotides encode 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; 294; 295; 296; 297; 298; 299; 300; 301; 302; 303; 304; 305; 306; 307; 308; 309; 310; 311; 312; 313; 314; 315; 316; 317; 318; 319; 320; 321; 322; 323; 324; 325; 326; 327; 328; 329; 330; 331; 332; 333; 334; 335; 336; 337; 338; 339; 340; 341; 342; 343; 344; 345; 346; 347; 348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 358; 359; 360; 361; 362; 363; 364; 365; 366; 367; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377, or more HLA-restricted epitopes encoded by the ncRNAs selected from Table A or selected from Tables 1-41.

[0210] As used herein, the term “polynucleotide” as used herein refers to polymers of nucleotides of any length, including ribonucleotides, deoxyribonucleotides, analogs thereof, or mixtures thereof. This term refers to the primary structure of the molecule. Thus, the term includes triple-, double- and single-stranded deoxyribonucleic acid (“DNA”), as well as triple-, double- and single-stranded ribonucleic acid (“RNA”). It also includes modified, for example by alkylation, and / or by capping, and unmodified forms of the polynucleotide. More particularly, the term “polynucleotide” includes polydeoxyribonucleotides (containing 2-deoxy-D-ribose), polyribonucleotides (containing D-ribose), including tRNA, rRNA, hRNA, siRNA and mRNA, whether spliced or unspliced, any other type of polynucleotide which is an N- or C-glycoside of a purine or pyrimidine base, and other polymers containing normucleotidic backbones, for example, polyamide (e.g., peptide nucleic acids “PNAs”) and polymorpholino polymers, and other synthetic sequence-specific nucleic acid polymers providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA. In some embodiments, the polynucleotide comprises an mRNA. In other aspect, the mRNA is a synthetic mRNA. In some embodiments, the synthetic mRNA comprises at least one unnatural nucleobase. In some embodiments, all nucleobases of a certain class have been replaced with unnatural nucleobases (e.g., all uridines in a polynucleotide disclosed herein can be replaced with an unnatural nucleobase, e.g., 5-methoxyuridine). In some embodiments, the polynucleotide (e.g., a synthetic RNA or a synthetic DNA) comprises only natural nucleobases, i.e., A, C, T and G in the case of a synthetic DNA, or A, C, T, and U in the case of a synthetic RNA.

[0211] In some embodiments, the polynucleotide of the present invention is a messenger RNA (mRNA).

[0212] In some embodiments, the polynucleotide is inserted in a vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector. Typically, the vector is a viral vector which is an adeno-associated virus (AAV), a retrovirus, bovine papilloma virus, an adenovirus vector, a lentiviral vector, a vaccinia virus, a polyoma virus, or an infective virus. Typically, the vector of the present invention include "control sequences", which refers collectively to promoter sequences, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites ("IRES"), enhancers, and the like, which collectively provide for the replication, transcription and translation of a coding sequence in a recipient cell. Not all of these control sequences need always be present so long as the selected coding sequence is capable of being replicated, transcribed and translated in an appropriate host cell. Another nucleic acid sequence, is a "promoter" sequence, which is used herein in its ordinary sense to refer to a nucleotide region comprising a DNA regulatory sequence, wherein the regulatory sequence is derived from a gene which is capable of binding RNA polymerase and initiating transcription of a downstream (3'-direction) coding sequence. Transcription promoters can include "inducible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), "repressible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc ), and "constitutive promoters”.

[0213] In some embodiments, the dark antigen or polynucleotide of the present invention can be conjugated to at least one other molecule. Typically, said molecule is selected from the group consisting of polynucleotides, polypeptides, lipids, lectins, carbohydrates, vitamins, cofactors, and drugs.

[0214] Typically, the active ingredient of the present invention (i.e. the polypeptide or polynucleotide) is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. The term "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0215] In some embodiments, the dark antigen or polynucleotide of the present invention is formulated with lipidoids. The synthesis of lipidoids has been extensively described (see Mahon et al., Bioconjug Chem. 201021:1448-1454; Schroeder et al., J Intern Med. 2010267:9-21; Akinc et al., Nat Biotechnol. 2008 26:561-569; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Siegwart et al., Proc Natl Acad Sci US A. 2011 108:12996-3001). While these lipidoids have been used to effectively deliver double stranded small interfering RNA molecules in rodents and non-human primates (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Frank-Kamenetsky et al., Proc Natl Acad Sci USA. 2008 105:11915-11920; Akinc et al., Mol Ther.

[0216] 2009 17:872-879; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Leuschner et al., Nat Biotechnol. 2011 29: 1005-1010), the present disclosure describes their formulation and use in delivering polynucleotides.

[0217] In some embodiments, the dark antigen or polynucleotide of the present invention is formulated using one or more lipid-based structures that include but are not limited to liposomes, lipoplexes, or lipid nanoparticles (Paunovska, Kalina, David Loughrey, and James E. Dahlman. "Drug delivery systems for RNA therapeutics." Nature Reviews Genetics (2022): 1-16). Liposomes are artificially-prepared vesicles which can primarily be composed of a lipid bilayer and can be used as a delivery vehicle for the administration of pharmaceutical formulations. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which can be hundreds of nanometers in diameter and can contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which can be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which can be between 50 and 500 nm in diameter. Liposome design can include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis. Liposomes can contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations. As a non-limiting example, liposomes such as synthetic membrane vesicles are prepared by the methods, apparatus and devices described in US Patent Publication No. US20130177638, US20130177637, US20130177636, US20130177635, US20130177634, US20130177633, US20130183375, US20130183373 and US20130183372. In some embodiments, the liposomes are formed from 1, 2-di oleyloxy -N, N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, Wash.), l,2-dilinoleyloxy-3 -dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[l,3]-dioxolane (DLin-KC2-DMA), and MC3 (as described in US20100324120) and liposomes which can deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, Pa.). The polypeptide of polynucleotide of the present invention can be encapsulated by the liposome and / or it can be contained in an aqueous core which can then be encapsulated by the liposome (see International Pub. Nos. W02012031046, W02012031043, W02012030901 and W02012006378 and US Patent Publication No. US20130189351, US20130195969 and US20130202684).

[0218] In some embodiments, the polynucleotide of the present invention is formulated with stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy. 1999 6:271-281; Zhang et al. Gene Therapy. 1999 6:1438-1447; Jeffs et al. Pharm Res. 200522:362-372; Morrissey et al., Nat Biotechnol. 2005 2:1002-1007; Zimmermann et al., Nature. 2006441:111-114; Heyes et al. J Contr Rel. 2005 107:276-287; Semple et al. Nature Biotech. 201028:172-176; Judge et al. J Clin Invest. 2009 119:661-673; deFougerolles Hum Gene Ther. 2008 19:125-132; U. S. Patent Publication No US20130122104). The original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al. and is referred to as the spontaneous vesicle formation method. The liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide. As an example a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2-dioleyloxy-N, N-dimethylaminopropane (DODMA), as described by Jeffs et al. As another example, certain liposome formulations contain, but are not limited to, 48% cholesterol, 20% DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2-distearloxy-N, N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3 -dimethylaminopropane (DLenDMA), as described by Heyes et al.

[0219] In some embodiments, the polynucleotide of the present invention is formulated in a lipid nanoparticle such as those described in International Publication No. W02012170930. Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid. The lipid can be selected from, but is not limited to, DLin-DMA, DLin-K-DMA, 98N12-5, C 12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In some embodiments, the lipid is a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid can be the lipids described in and / or made by the methods described in US Patent Publication No. US20130150625. As a non-limiting example, the cationic lipid can be 2-amino-3 -[(9Z, 12Z)-octadeca-9, 12-dien- 1 -yloxy]-2- { [(9Z,2Z)-octadeca-9, 12-dien- 1 -yloxy]methyl (propan- l-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en-l-yloxy]-2-{[(9Z)-octadec-9-en-l-yloxy]methyl(propan-l-ol (Compound 2 in US20130150625); 2-amino-3 -[(9Z, 12Z)-octadeca-9, 12-dien- 1 -yloxy]-2- [(octyloxy)methyl]propan-l-ol (Compound 3 in US20130150625); and 2-(dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-l-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-l-yloxy]methyl (propan- l-ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof. Nanoparticle formulations of the present disclosure can be coated with a surfactant or polymer in order to improve the delivery of the particle. In some embodiments, the nanoparticle is coated with a hydrophilic coating such as, but not limited to, PEG coatings and / or coatings that have a neutral surface charge. The hydrophilic coatings can help to deliver nanoparticles with larger payloads such as, but not limited to, polynucleotides within the central nervous system. As a non-limiting example nanoparticles comprising a hydrophilic coating and methods of making such nanoparticles are described in US Patent Publication No. US20130183244.

[0220] As used herein, the expression "therapeutically effective amount" is meant a sufficient amount of the active ingredient of the present invention to induce an immune response at a reasonable benefit / risk ratio applicable to the medical treatment.

[0221] The dark antigen or polynucleotide of the present invention as described herein may be administered as part of one or more pharmaceutical compositions. The term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and / or excipients. The pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the peptides of the present invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. In particular, the dark antigen or polynucleotide of the present invention as described herein are particularly suitable for preparing vaccine composition. For the purpose of the present invention, the term "vaccine composition" is intended to mean a composition which can be administered to humans or to animals in order to induce an immune system response; this immune system response can result in the activation of certain cells, in particular antigen-presenting cells, T lymphocytes and B lymphocytes. Accordingly, in some embodiments, the vaccine composition of the present invention comprises an adjuvant. The term “adjuvant” can be a compound that lacks significant activity administered alone but can potentiate the activity of another therapeutic agent. In some embodiments, the adjuvant is alum. In some embodiments, the adjuvant is Incomplete Freund’s adjuvant (IF A) or other oil based adjuvant that is present between 30-70%, preferably between 40-60%, more preferably between 45-55% proportion weight by weight (w / w). In some embodiments, the vaccine composition of the present invention comprises at least one Toll-Like Receptor (TLR) agonist which is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists.

[0222] The dark antigen or polynucleotide of the present invention of the present invention may be administered to the subject by any route of administration and in particular by oral, nasal, rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active agent which is being used.

[0223] The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

[0224] Figure 1: Transcriptomic characterization of colorectal premalignant lesions.

[0225] a. Pie charts representing the proportion of ncRNA among, from left to right: (1) all detected transcripts in the original cohort, (2) among differentially expressed transcripts between tissue types of the GSE76987, (3) among differentially expressed transcripts between serrated and adenomatous polyps from the original cohort and (4) among differentially expressed transcripts between Fl and F2 / F3 samples from the original cohort, b. Heatmap representing two- dimensional unsupervised hierarchical clustering of non coding RNA differentially expressed between Fl and F2 / F3 samples from the original cohort. The sample similarity (right dendrogram) and expression pattern similarity (top dendrogram) are shown. Annotation bars are included for belonging to the Fl group, lesion type, advanced samples and belonging to the CD8hlghgroup.

[0226] Figure 2: Immune profiles of samples expressing different levels of non coding RNA. a. Violin plots representing the sum of strong binder peptides expressed by each sample from the ncLow and ncHigh groups. A strong binder peptide (8-10mer) binds with an ic50 < 500nM (predicted with NetMHCPan 4.1) to the respective MHC Class I complex. Wilcoxon Ltest. b.

[0227] Violin plots representing the distribution of tissue surface occupied by TLS (left, Wilcoxon t-test)) and bar plots representing the distribution of TLS classes (right, chi-square test) between ncLow and ncHigh samples, c. Violin plots representing the distribution of cell densities at the invasive margin for B cells, Plasma cells, CD4+T cells and CD8+T cells between ncLow and ncHigh samples. Wilcoxon Ltest. d. Violin plots representing the distribution of TLS and immune cell type abundance score between ncLow and ncHigh samples. TLS score was calculated on a published transcriptomic signature, immune cell type abundance was calculated using the ConsensusTMEtool. Wilcoxon Ltest. e. Pie charts representing Distribution of ncHigh and ncLow samples across frequency groups. Fisher’s exact test.

[0228] Figure 3: Immune profiles and precancerous lesion development rate.

[0229] a. Pie charts representing the distribution of frequency groups in CD8lowand CD8hlghsamples. Fisher’s exact test. b. Violin plots representing the distribution of the surface of tissue occupied by TLS (top, Wilcoxon t-test)) and bar plots representing the distribution of TLS classes (bottom, chi-square test) between frequency groups in all precancerous lesions (left), serrated polyps (centre) and adenomatous polyps (right).

[0230] Figure 4: Immune profiles and polyp development rate

[0231] Heatmap representing two-dimensional unsupervised hierarchical clustering of immunohistochemistry derived cell densities in the invasive margin of adenomatous polyps from the original cohort. Samples are split by frequency group. The cell densities similarities (left dendrogram) and sample similarities (top dendrogram) are shown. Annotation bars are included for frequency group and lesion type. Results of Wilcoxon t-test comparing densities across frequency groups are presented on the right. Figure 5: ncRNA, CD8 infiltration and frequency groups

[0232] a. Pie charts representing the proportion of dysregulated ncRNA within total ncRNA following differential expression analysis between Fl and F2 / F3 samples ( left) and CD8lowand CD8hlghsamples (right), b. Pie chart representing the proportion of ncRNA dysregulated between Fl and F2 / F3 samples frequency within ncRNA dysregulated among CD8 groups, c. Scheme summarizing the main finding of this study.

[0233] Figure 6: Intersection and Combination. A. Intersection when combining Cl, C2, C3, C4, C5 and C6. B. Results when combining sets Cl, C2, C3, C4, C5 and C6 based on intersect mode.

[0234] EXAMPLE:

[0235] Example 1:

[0236] Methods:

[0237] Public data

[0238] RNA expression data (raw counts) of several public data sets (GSE44076, GSE117606, GSE117607 and GSE76987) and their associated clinical data available were downloaded through the GEO portal (https: / / www.ncbi.nlm.nih.gov / geo / ).

[0239] Clinical cohort constitution

[0240] The original cohort was retrospectively selected from adults who underwent surveillance colonoscopy or surgery for polyp resection between 2012 and 2020 at the Cliniques Universitaires Saint-Luc in Bruxelles. As presented in Table 43, 26 patients were selected. Each patient has been surgically treated for colorectal precancerous lesions and / or cancer one to seven times. Each time, between one and 12 lesions have been removed for a total of 135 lesions. For each lesion, eight fixed-formalin paraffin embedded tissue slides were collected for DNA and RNA extraction and H4C staining. For annotation purpose, a scan of hematoxylin & eosin (H& E) staining was also collected. When available, two slides of healthy tissue per patient were also selected for germline reference (WES).

[0241] Table 43: Patients characteristics: Patients os 261

[0242] Age. mean < SD' 64,(> W)5i

[0243] female 9 (34.6)

[0244] Male 17 (654 >

[0245] Body mass index, mean (SD) 26.2 (5.30)

[0246] Follow-up i sears x mean i SD I 4.‘)S 12.231

[0247] Lesion number, mean (SD) 5.81 (4.73)

[0248] Cohort annotation

[0249] Colorectal lesions type, grade and area were annotated on an H& E staining by an expert pathologist. In the case of a lesion composed of distinct areas identified as LG AP and HG AP by the pathologist, the whole lesion was considered as one and graded as HG AP for DNA and RNA extraction. For IHC analysis, LG AP and HG AP areas were annotated and analysed separately.

[0250] Frequency group

[0251] Patients were classified into three frequency group Fl F2 and F3 based on the ratio between the total number of lesions surgically removed during their follow-up and the total length of this follow-up (not shown).

[0252] RNA and DNA extraction

[0253] RNA and DNA were isolated from FFPE tissue slides using NucleoSpin totalRNA FFPE XS and NucleoSpin DNA FFPE XS kits (MACHEREY-NAGEL), respectively, and according to the manufacturer’s instructions. RNA concentration was measured using a spectrophotometer NanoDrop 2000 (Thermofisher Scientific). DNA concentration was measured using the Qubit 4 Fluorometer (Thermofisher Scientific).

[0254] RNA sequencing and alignment

[0255] RNA-sequencing was performed using QuantSeq 3’ RNA-755 Seq Library Prep Kit FWD for Illumina (75 single-end) with a read depth of 8M (Sidra Medicine, Doha, Qatar). Single samples were sequenced across four lanes, and the resulting FASTQ files were merged by sample. Quality trimming is performed to remove adapter sequences and polyA tails. Then trimmed reads were aligned to human genome GRCh37 / hg37 (Genome Reference Consortium Human Build 37) using STAR 2.6. Id. FeatureCounts v2.0.0 was used to generate the raw counts. Raw expression data were normalized to size factor effects using R package DESeq241, and patient presenting particularly low total normalized count were removed as quality control. RNA classes were provided by Ensembl.

[0256] Differential expression analysis

[0257] Transcript wise differential expression analysis was performed using the R package DESeq2.

[0258] CMS classification

[0259] CMS classification was performed on normalized transcripts counts using the R package CMScaller42, using the ’Nearest Template Prediction’ algorithm to predict which CMS class described the sample best. Sample that could not be associated with a CMS class were annotated as "Indeterminate".

[0260] ConsensusTME scoring

[0261] ConsensusTME was carried out on normalized RNAseq counts using the R package ConsensusTME43. Each score is determined based on a consensus gene sets. Gene sets are then used within a single-sample Gene Set Enrichment Analysis framework to provide normalized enrichment scores for each of the cell types representing the relative abundance of cell types across multiple samples.

[0262] Immunoediting score

[0263] The immunoediting score was calculated applying the method published by Rooney et al., 201544. From the TCGA COAD reference dataset the average number of immunogenic mutations per non-silent mutation for each trinucleotide context Bswas derived. Then for each spectrum s, the expected number of non-silent mutations per silent mutation, Ns, was estimated. Given the set of silent mutations, Si and its corresponding mutation context, s(m), in the sample i, the expected number of non-synonymous Npred,i and immunogenic mutations Bpred,i were calculated as:

[0264]

[0265] The immunoediting score represented the ratio of expected to observed immunogenic mutations per non-silent mutation.

[0266] Immunogenicity estimation To estimate the number of putative neo-epitopes from ncRNA the cDNA sequence for each transcript was extracted from Ensembl and translated to protein sequences using the canonical ATG trinucleotide sequence as starting point. To generate all possible 8,9,10 mers a respective window was moved over the entire protein sequence to produce these peptides (redundant peptides were discarded). Finally, for each ncNA and all its resulting peptides together with the known HLA types per patients the immunogenicity score was calculated using NetMHCpan 4.1. Strong binders were defined with an ic50 < 500 nM. Then all strong binders per ncRNA presenting a z-score log2 expression > 1.5 were summed up per sample to define a strong binder score.

[0267] T cell and B cell repertoire

[0268] The Exome-seq reads were realigned on the unspliced genomic regions of several TCR and IG chains: TCRa, TCRb, TCRg, TCRd, IgH, IgK, and IgL, using the tool MiXCR, which considers the hypermutated context of the CDR3 regions to transform the raw data into T cell and B cell clonotypes.

[0269] Clonality scores calculation

[0270] Entropy (H) is calculated on bulk RNAseq data by a standard Shannon entropy calculation with log base 2, using the tool MiXCR. The equations are below:

[0271] Shannon Entropy: H(x)= -XP(x)log2 [P(x)]

[0272] For a sequence x, P(x) = sequence count / total count

[0273] The Shannon Entropy was normalized so that it can assume a value between 0 and 1. The normalized Shannon Entropy is referred to as Pielou’s Eveness and it is calculated as below: Pielou’s Eveness: J = H / log(S)

[0274] where S is the number of unique TCR / CDR3 sequences.

[0275] Clonality is calculated as the inverse of the normalized entropy calculation:

[0276] Clonality score = 1 - J

[0277] The sequence count is equal to the unique number of found TCR clones per sample.

[0278] The total count is equal to the total number of found TCR clones per sample.

[0279] Samples were split between low and high clonality score using a threshold based on clonality score distribution across samples.

[0280] Whole exome sequencing and alignment Standard Whole exome sequencing was performed (Sidra Medicine, Doha, Qatar). WES reads were aligned to the human genome GRCh38 / hg38 (Genome Reference Consortium Human Build 38) using BWA aligner. Duplicated reads were removed using GATK preprocessing. SNV were called using Mutect2 (REF XXX)

[0208] , Several filtering steps were then applied to generate MAF files containing single nucleotide variant per sample. Somalier analysis was performed to rate the relatedness of samples and check the proper germline sample - somatic sample association.

[0281] Oncoplot generation

[0282] Oncoplot and total mutation burden data were generated from the MAF file using the R package maftools45.

[0283] Immunohistochemistry slide preprocessing

[0284] For deparaffinization, FFPE slides of tonsil and colorectal cancer (CRC) were incubated at 56°C for four hours, then soaked in Clearene, rehydrated by immersion in a graded ethanol series (100%, 90%, 70%, 50% and distilled water) and finally fixed in 10% Neutral buffered formalin.

[0285] Multiplex Immunofluorescence

[0286] Staining

[0287] MxIF stainings were performed using the Opal-TSA technology (Opal Polaris 7 Color IHC Detection Kits, Akoya Biosciences). Staining was performed on the autostainer Bond RX (Leica Biosystems) following protocols recommended by Akoya Biosciences. Slides were stained in a sequential way using antibody retrieval, antibody blocking solution, primary antibodies, secondary polymers and opal fluorochromes. Finally, slides were manually counterstained with spectral DAPI (Akoya Biosciences) and mounted using the mounting medium ProLong™ Diamond Antifade Mountant (Thermofisher Scientific).

[0288] Image acquisition

[0289] Stained slides were digitised with the 20X lens of the PhenoImager HT (0.5 pm / pixel, Akoya Biosciences) under fluorescent conditions, providing whole slide RGB images. Images were then imported in the Phenochart software (Akoya Biosciences) to select and extract areas presenting tissue. Finally, specific signal from each fluorochrome was extracted from the original image (not shown), creating a seven-channel image (not shown) which was further analysed using the DP software HALO (Indicalabs).

[0290] Image analysis

[0291] We developed an end-to-end image analysis pipeline based on convolutional neural networks using HALO and its HALO Al™ image analysis add-on (Indica Labs) to segment the tissue in regions of interest (ROIs) and quantify cell densities in these ROIs. First, representative training regions for epithelial areas, stromal areas and TLSs were annotated across samples. These annotations were used to train a DenseNet architecture (HALO Al™ tissue classifier) using only DAPI, CD3 and CD20 signals, which resulted in the detection of epithelial and stromal compartments as well as TLSs (Not shown). Only TLSs presenting an area > 25,000 mm2 were included in the following analyses. Pathologist annotations indicating the lesion area (referred as centre of the tumour, CT) were then reported to the tissue, and a 1mm wide margin was built around CT (not shown). Subsequently, this margin was divided into stromal and epithelial compartments using our tissue classifier. The stromal compartment resulted in the IM ROI (not shown). For each compartment, cells were detected on the basis of the DAPI signal using a CNN-based nuclei segmenting tool (HALO Al™ nuclei seg) trained on nuclei annotations for optimal detection. Finally, this segmentation was integrated into a software-based module (Highplex FL module), and positivity thresholds were set for each marker, attributing a phenotype to each cell. Cell densities were exported and processed with the software R.

[0292] Multiplex Immunohistochemistry

[0293] Staining

[0294] After preprocessing and an antibody retrieval step, FFPE slides were stained using the Brightplex technology (Veracyte). Briefly, slides were stained for the first marker of the panel using ImmPACT AMEC Red Substrate (Vector Laboratories) and the Bond RX following a Brightplex specific protocole. Slide were then mounted using an aqueous mounting medium (Vectamount, Vector). Whole slide images were digitised at 20X using the slide scanner Nanozoomer 2.1 (0.46 pm / pixel, Hamamatsu) before unmounting the slides using a 56°C water bath. The chromogenic staining was then removed using ethanol and the antibody was stripped using a denaturing solution and a heating step. The tissue slide can then undergo another round of this staining, using the next antibody. The following antibodies were used: CD3, CD8, TIM3, PD1, TCF1, PDL1, Ki67 and Cytokeratin. Staining conditions are subject to a confidentiality agreement with Veracyte. Image analysis

[0295] After acquisition of the eight whole slide images corresponding to each marker (not shown), images were imported on the image analysis software HALO and the specific signal of each marker was extracted using a deconvolution algorithm. Nuclei signal was extracted from the haematoxylin signal of the first staining cycle. All extracted signals were then merged into a nine-channel, immunofluoresence-like, image (not shown). CT, IM and TLS ROIs from the MxIF analysis were reported and the same analysis pipeline was applied, resulting in cell density extraction.

[0296] Visualization and Statistical analysis

[0297] All visualization and statistical analysis were performed using the R software (version 4.1.3). Unsupervised Hierarchical clustering and heatmaps were generated using the R package ComplexHeatmap. The relationship between two categorical variables was estimated with the Chi-squared test or Fisher’s exact test depending on sample size. The relationship between two quantitative variables was estimated with the Mann-Whitney U test. Correlations were computed with Pearson’s correlation. A p-value threshold of 0.05 was chosen for significance. No statistical methods were used to predetermine sample size.

[0298] Results:

[0299] Polyp development rate and colorectal premalignant pathways

[0300] To identify parameters associated with colorectal precancerous lesion development rate, we deeply phenotyped an original dataset comprising 135 carefully annotated colorectal lesions from 26 patients, including polyps and invasive carcinoma. The samples underwent multimodal phenotyping, including whole exome sequencing, RNA sequencing and multiplex immunohistochemistry (IHC) (data not shown). The 26 patients presented a heterogeneous history of colorectal lesions, with a total number of lesions ranging from 1 to 14, and a number of time points at which they have been treated for lesions going from 1 to 7 (data not shown).

[0301] Except for one case of Lynch Syndrom, patients did not have any known risk factor responsible for a high rate of polyp development rate. Polyps were histologically categorised into the two main precancerous pathways: serrated polyps (SPs), consisting of hyperplastic polyps (HPs) and sessile serrated lesions (SSLs), and adenomatous polyps (APs), consisting of low-grade (LG APs) and high-grade adenomatous polyps (HG APs). Additionally, Advanced status was attributed to SPs with a size > 10 mm while APs were classified as advanced when positive for at least one of the following criteria: HG AP, size > 10 mm or villous histology.

[0302] To study polyp development rate, we split patients into three groups based on their number of lesions developed per year of follow-up, called frequency groups. First group (Fl) was associated with a low number of polyps per year (< 0.7 polyp / year) and no recurrence, while F2 and F3 presented patients with both recurrence of lesions and more than 0.7 polyp / year (data not shown). Interestingly, Fl and F2 patients presented similar follow-up periods while F3 patients displayed very short follow-up time (data not shown).

[0303] Similar proportions of SPs and APs were found across frequency groups (data not shown), suggesting that polyp frequency is not associated with a specific precancerous pathway (P = 0.641).

[0304] Mutational analysis

[0305] We performed the mutational analysis of our samples based on whole exome sequencing data and presented the results in the form of an oncoplot (data not shown). Within a given patient, the lesions shared a low proportion of mutations, supporting the sporadic and independent origin of these lesions (data not shown). As expected, the major driver mutations were significantly associated with specific precancerous pathways (P = l. O24xlO'10). Indeed, BRAF mutations was found in 92% of serrated samples and 0% of adenomatous samples. APC, KRAS and TP53 mutations were found in 0% of serrated samples and 73%, 37% and 7% of adenomatous samples, respectively. Tumour mutational burden (TMB) was then evaluated, revealing three samples with very high TMB due to lynch syndrome, sporadic MSI, and POLE mutation, respectively. Malignant lesions showed higher TMB than premalignant ones, and advanced APs showed higher TMB than non-advanced APs (data not shown).

[0306] Transcriptomic profiles

[0307] To first investigate the transcriptomic profiles of our samples, we evaluated their Consensus molecular signature (CMS, Guinney et al. 2015) profiles, revealing increased frequencies of CMS1 and CMS4 within serrated precancerous lesions and increased frequency of CMS2 within adenomatous precancerous lesions (P=9.21xl0‘9). In contrast, no significant differences were observed in CMS categories within pathways or between polyp frequency (data not shown). Then, to visualise the evolutionary trajectory of colorectal carcinogenesis from normal epithelium to the metastasis, we compiled gene expression transcriptomic data from multiple datasets and performed a tSNE analysis. First, several public datasets including samples from healthy colon, SP, AP, primary carcinoma and adjacent normal mucosa were pooled (n = 582 samples, data not shown), their tSNE coordinate evoking a continuum from normal to adjacent healthy tissue to precancerous and finally cancerous samples. Second, a dataset consisting of colorectal RNAseq data from our team was analysed, including the original cohort previously presented as well as other primary and metastatic CRC (resulting in 264 samples divided into SP, AP, primary carcinoma and distant metastasis, data not shown). tSNE analysis based on gene expression profiles highlighted a stereotyped progression from early carcinogenesis to metastatic CRC, with the two pre-cancer pathways (serrated and adenomatous) presenting distinct gene expression profiles.

[0308] Differential transcript expression analysis

[0309] We performed differential expression analysis of samples from Fl patients versus other samples (from F2 / F3 patients) to identify differentially expressed transcripts (DETs) associated with polyp development rate (DEI). To investigate the presence of these DETs across colorectal carcinogenesis stages, we analysed another public dataset (GSE76987) consisting of RNAseq data from 86 samples including several colon tissue types: healthy mucosa, AP, SSLs, and cancer samples and their adjacent mucosa. Differential transcript analysis was performed between each tissue type (DE2). We observed that transcripts upregulated in Fl were found upregulated in earlier stages of carcinogenesis (e.g. overexpressed in healthy tissue versus cancer or AP versus cancer) while transcripts upregulated in F2+F3 were upregulated in advanced stages of the carcinogenesis (eg, cancer versus SP). Hierarchical clustering analysis of DETs from DEI revealed two clusters of samples presenting very different expression patterns (data not shown). Strikingly, when looking at RNA classes of DETs between Fl and F2 / F3, we observed that transcripts upregulated in Fl were strongly enriched in ncRNA: ncRNA represented 77.2% of upregulated transcripts in Fl versus 29.7% of upregulated transcripts in F2 / F3 (data not shown).

[0310] Using total gene expression data and differential expression data, we found 38.3% of ncRNA across the genome, 30.3% of ncRNA among DETs between malignant and premalignant tissues and 28% of ncRNA among DETs between precancer pathways (SP vs AP). In contrast, among the 634 DETs between Fl and F2 / F3 samples, we found an over-representation of ncRNA (59%) (P=0.00001) (Figure la)

[0311] Hierarchical clustering of the 377 differentially expressed ncRNA between Fl and F2F3 samples separated samples into 2 clusters: ncLow (majority of underexpressed ncRNA) and ncHigh (majority of overexpressed ncRNA) (Table A). 70 ncRNA were overexpressed in ncLow samples versus 307 ncRNA in ncHigh samples (Figure lb). The ncLow and ncHigh clusters did not appear to be associated with a specific precancerous pathway (data not shown).

[0312] Overall, our findings suggest that Fl samples show more similarities toward healthy colon tissue, while F2 / F3 samples appear more similar to cancer samples. Fl samples also appear strongly enriched in ncRNA when compared to F2 / F3 samples.

[0313] ncRNA and immune microenvironment

[0314] As ncRNA are known to be a potent source of immunogenic antigens capable of eliciting an antitumor immune response, we then investigated the immunogenicity of the differentially expressed ncRNA between Fl and F2 / F3. We evaluated the predicted capacity of ncRNA derived peptides (8-1 Omer) to bind their respective MHC Class I complex, often used as an indication of the peptide's potential immunogenicity. Said peptides are depicted in Tables 1-42. The number of strong binder peptides per sample was then calculated. Interestingly, ncHigh samples expressed 3.81 times more strong binder peptides compared to ncLow samples. Overall, the ncHigh samples had higher predicted immunogenicity compared to the ncLow samples (wilcoxon, p=1.7 10'6) (Figure 2a).

[0315] As higher immunogenicity can lead to higher immune recruitment and activation, we evaluated the immune microenvironment of ncLow and ncHigh samples using two multiplex IHC panels. First, the presence of the main adaptive immune cell type was evaluated using six-marker multiplex immunofluorescence (MxIF): B cells (CD20+), plasma cells (MUM1+), T cells (CD3+), CD4+T cells (CD3+CD4+), CD8+T cells (CD3+CD8+) and regulatory T cells (CD3+CD4+FoxP3+) were identified (data not shown). Second, the functional status of T cells was assessed using eight-marker multiplex IHC (MxIHC), including T cell markers (CD3 and CD8), exhaustion markers (TIM3, PD1, PDL1, TCF1) and proliferation marker (Ki67) in addition to the epithelial marker cytokeratin (data not shown). For each lesion, the centre of the tumour (CT) and the invasive margin (IM) were assessed based on pathologist annotations (data not shown).

[0316] Tertiary lymphoid structures (TLSs) were classified into unstructured, intermediate and structured based on CD3 / CD20 patterns and their mature status was determined using PD1 and Ki67 staining to assess the presence of a germinal centre (data not shown). Interestingly, the presence of mature TLSs was associated with higher IG and TRAB clonality as well as increased B cell density in the IM of both SPs and APs (data not shown). Samples in the ncHigh group had a significant increase in the percentage of tissue surface occupied by TLSs (P=0.01) combined with a significant increase in the proportion of mature TLS (P = 9.30xl0'5, Figure 3b). We quantified the IM densities (cells / mm2) of B cells, plasma cells, CD4+T-cells, and CD8+T cells and found significantly higher densities in ncHigh samples compared to ncLow ones, except for plasma cells where the trend was still present (P = 0.051) (Figure 3c).

[0317] Using RNAseq data, we then estimated a TLS score using a published TLS signature (ref) and the relative abundance of different immune cell types using a deconvolution method for the tumour microenvironment based on gene expression data (TMEconsensus) (Figure 3d). As SPs and APs presented very distinct transcriptomic profiles (data not shown) and there was not enough ncHigh SPs, this analysis was performed separately for APs only. We confirmed a significant increase in TLS (P=0.026) and of B-cells, plasma cells, CD4+T cells, CD8+T cells and dendritic cells in ncHigh APs (all P<0.01) (Figure 3d).

[0318] Finally, it should be noted that all (100%) of Fl lesions belonged to the ncHigh group, compared to only 18.3% of F2 / F3 lesions (P<0.0001), suggesting that the frequency group might also be associated with different immune TME (Figure 3e).

[0319] Polyp development rate and immune microenvironment

[0320] To investigate the immune TME across frequency groups, we first split our samples based on their total level of CD3+CD8+cytotoxic T cell densities, leading to CD80Wand CD8hlghsamples. Samples from Fl patients were overrepresented in CD8hlghsamples compared to CD81ow samples (35.1% versus 6.5%, respectively, P=0.0004) (Figure 3a). Similarly, 68.4% of Fl samples were CD8-high versus 21.5% and 21.9% for F2 and F3, respectively (p = 0.0004, data not shown). We then studied the immune contexture associated with the three polyp frequency groups. The Fl samples had a significant increase in the percentage of surface occupied by TLS compared to F2 or F3 (both P<0.01) (Figure 3b). Furthermore, Fl samples had a significant increase in the proportion of mature TLS compared to F2 or F3 (P = 3x1 O'8). Although similar results were found in the adenomatous samples, no significant difference was found in serrated lesions (Figure 3b). Preliminary observations of immune densities across frequency showed higher densities of adaptive immune cells in Fl samples compared to F2 and F3 samples in both pathways, as illustrated for the markers CD3, CD8, PD1, Ki67, and PDL1 (Figure 3c).

[0321] Differences between precancerous pathways TLS data supported the comparison of their respective immune TME profiles. Comparisons of SPs and APs immune profiles showed higher surface occupied by TLSs in SPs and overall higher CT and IM immune densities in APs (data not shown). Intrapathway analysis revealed no differences in the main immune populations in SPs and APs, both in IM and CT (data not shown). The only significant differences were found in the CT of APs with the decrease of plasma cell densities and the increase of Treg densities from non-advanced to advanced APs. In consequence, due to their pathway-specific profiles, immune TMEs of precancerous samples were analysed in each pathway separately.

[0322] Unsupervised hierarchical clustering of all samples according to the densities of all subpopulations quantified by digital pathology were performed both in CT and IM for SP and AP samples (Figure 5 and data not shown).

[0323] The densities of PDL1+cells were higher in Fl polyps compared to F2 and F3 polyps, independently of the precancerous pathway. In SPs, both CT and IM of Fl samples presented higher immune densities for CD8+cells and their various subsets compared to both F2 and F3. Similar observations were made for B cells while plasma cells densities were lower in F3 compared to both Fl and F2. CD4+T cell densities were stable in SPs between frequency groups, both in CT and in IM. In the CT of APs, the main immune cell densities were similar across frequency groups. In the IM of APs, the densities of most immune cells and their associated subsets decreased from Fl to F2 to F3. The results of APs were supported by deconvolution analysis based on RNAseq data (data not shown). This analysis also highlighted an enrichment of Fl APs in myeloid cells (neutrophils; Ml and M2 macrophages, etc.).

[0324] Due to the profiles of frequency groups, two main hypotheses could explain the immune TME variations described above. On one hand, differences could be attributed to a modification of the immune TME appearing through recurrences (samples from time point tl, t2, t3... called tl+). On the other hand, these differences could be observed as early as tO, suggesting preexisting immune TME differences. To answer this question, we split F2 and F3 samples between tO and tl+samples. In APs, we observed that differences between Fl samples (which are only tO samples) and F2t0 and F3tO samples were still present, while immune densities did not vary between tO and tl+both within F2 and F3 samples (data not shown). Finally, we also observed that no difference of proportions of CD8lowand CD8hlghsamples were found between F2F3tO and F2F3tl+(data not shown). Overall, this data show that the higher densities of immune observed in Fl samples compared to F2 and F3 are present as early as tO, and that the immune TME does not vary along with recurrence.

[0325] ncRNA differentially expressed CD8hl8hand CD8lowsamples are enriched in ncRNA differentially expressed between polyp frequency groups

[0326] While 3.8% of ncRNA were differentially regulated between Fl and F2 / F3, this number fell to 0.7% when looking at differentially regulated ncRNA between CD8hlghand CD8lowgroups (Figure 5a). Strikingly, 47.9% of these 0.7% ncRNA were found to be also significantly dysregulated between Fl and F2 / F3 pre-cancer samples (Figure 5b). Moreover, 100% of these ncRNA were upregulated both in Fl and CD8hlgh(P<10‘15). This strong overlap suggests intricate interactions between ncRNA expression, immune infiltration and polyp development rate. Overall, our findings support interactions between polyp development rate, ncRNA expression, immunogenicity, TLS maturation levels, IG and TRAB clonality and adaptive immune densities (Figure 5c).

[0327] Discussion:

[0328] Mechanisms shaping the precancerous phases of colorectal carcinogenesis remain poorly understood, hindering the development of consensus screening guidelines, early therapies and prophylactic approaches. By performing integrative multimodal phenotyping of a unique cohort of patients developing precancerous colorectal lesions at low (Fl patients) and high (F2 and F3 patients) rates (n=135) and of samples from normal mucosa, pre-cancers and tumours (n=846), we established evolutionary trajectories of cancer and precancer immune contexture. We revealed that polyp development rate and colorectal cancer risk are associated with the expression of ncRNA and the immune TME. After investigating the mutational and transcriptomic profile of our samples, we showed that DETs between Fl and F2 / F3 samples, and particularly transcripts upregulated in Fl samples, were enriched in ncRNAs. Additionally, transcripts upregulated in Fl samples were also found to be associated with normal and precancerous colon while transcripts upregulated in F2 / F3 were associated with more advanced carcinogenesis stages. Samples overexpressing ncRNA expressed more potential strong binder peptides, hinting toward increased immunogenicity. Additionally, higher TLS presence and maturation level, as well as higher adaptive immune cell density were also observed in these samples. Finally, we showed that Fl samples presented higher TLS maturation levels associated with higher immune cell density (both in CT and IM in SPs and only in the IM in APs), and that ncRNA upregulated in CD8hlghsamples strongly overlapped with ncRNA upregulated in Fl samples. Given these results, we propose that high ncRNA expression is associated with high adaptive immune recruitment and activation, resulting in low polyp development rates.

[0329] The prognostic impact of immune infiltrates has been demonstrated in various cancer types24'26, including colorectal cancer2at the earliest stages (stage I)4’27’28. We previously showed that the tumour microenvironment was a critical determinant of dissemination to distant metastasis29,30and of metastatic tumour development, where tumour evolution could be traced back to immune escaping clones31. These findings could also apply to the pre-malignant transformation and the initiation of lung squamous cell carcinoma11 12. The contribution of tumour intrinsic factors to the risk of carcinogenesis has been shown to be modest32, as compared to extrinsic carcinogens32or dysregulation of the immune microenvironment14’15’31. Our study showed that intrinsic characteristics of altered pre-neoplastic cells, including oncogenic mutation, molecular precancerous pathway, CMS molecular classification, were not main drivers of polyp development rates. In contrast, intrinsic tropism of the pre-cancer microenvironment, including ncRNA expression, immunogenicity patterns of these dark antigens and local adaptive immunity such as TLS maturation level, CD8 and PDL1 expression in early lesions were associated with polyp development rate and colorectal cancer risk. Additionally, these differences were observable as soon as the first time point (tO), suggesting preexisting discrepancies between patients. Dysregulation of these parameters were associated with a major increase in the number of polyps per year. Our results align with recent studies on colorectal precancerous lesions on numerous observations. Enrichment of SPs in CMS1 and APs in CMS2 were previously described33. Similar results in terms of driver mutations and TMB across serrated and adenomatous pathways were observed, with the TMB being surprisingly higher in AP compared to SP despite the serrated pathway being associated with hypermutated phenotypes15. Increase of regulatory T cells densities but not exhaustion markers with AP progression were also described, along with a transcriptomic continuum from normal tissue to precancerous lesion to invasive adenocarcinoma14. One study in particular34modelled CRC evolution and found that, akin to our Fl samples compared to F2 / F3 samples, benign adenomas were more immunogenic and presented higher CD8+T cells while expressing more PDL1 when compared to adenomas that progressed toward invasive carcinoma. The model also predicted that, due to their strong immunogenicity, benign adenomas were unable to overcome immune attack despite signs of immunosuppression. This result corroborates with the fact that Fl patients present a different profile than F2 / F3 patients as soon as tO, suggesting that the risk of developing cancer is very low for Fl patients. One could consider Fl patients as the basal state as their polyp frequency profile is found in the majority of patients without known risk factors20. Higher rate of polyps (F2 / F3 patients) and risk of CRC in patients with sporadic polyps seemed associated with immune defect. A global defect of immune patterns in CT and IM regions was observed in serrated lesions, and a localized defect of immune patterns to the margin and TLS in adenomatous lesions.

[0330] Most previous studies studying tumour specific antigens focused on canonical transcripts (such as tumor-testis antigens) and their potential mutations. However, these coding sequences represent less than 2% of the genome, and recent studies have shown that non canonical transcripts (including long ncRNA and pseudogene), also called dark matter, are a particularly potent source of tumour specific antigens9,10. Their shared and recurrent nature across tumours promise new opportunities for immunotherapies8,35. Furthermore, major clinical benefit of checkpoint immunotherapy was obtained in various settings of cancer treatment36, including combination immunotherapy in pMMR (MSS) CRC patients37. The positive results of immune checkpoint blockade therapy in neoadjuvant settings for colorectal cancer38,39reinforce its importance in pre-cancer settings. Up to now, the best opportunity to cure colorectal cancer patients remains early intervention. Our findings highlight the potential of immunotherapy and prophylactic immune modulation for early intervention in colorectal carcinogenesis.

[0331] We acknowledge that with 26 patients and 135 samples the cohort was of relatively small size. However, the constitution of such a unique cohort, particularly F2 / F3 patients who present a particularly rich colorectal lesion history despite no specific risk factor, is a necessary step toward a better understanding of underlying mechanisms. One consequence of the cohort size is that multimodal characterization could not be performed on specific subgroups which were limited in sample number. In particular, few SPs yielded enough RNA for RNAseq and few Fl samples yielded enough DNA for WES, preventing us from performing transcriptomic analysis within the serrated pathway or mutation comparison per frequency group, respectively. Besides its specific mutation profile, the Lynch patient did not present specific transcriptomic or immune specificities, which prompted us to integrate it within the cohort. Finally, F3 patients display very short follow up periods, which could explain their particularly high polyp frequency. Longer follow-up could see them regress to F2.

[0332] Together, our findings suggest that genomic alterations of non-coding genes can determine microenvironmental immune contexture of pre-cancer lesions and their ability to prevent detectable recurrence. These results provide putative mechanisms and rationale to assess the effects of immunotherapy and prophylactic immune modulation in pre-cancer settings. Additionally, guidelines for intervals between screening after diagnosis of precursor lesions vary considerably. As a result, some high-risk patients are not sufficiently monitored, while less-risk patients are subjected to excessive surveillance40. This study provide support for investigation of new markers potentially helping to establish a more personalized and suitable follow-up such as ncRNA expression levels, presence of mature TLS or adaptive immune density.

[0333] Example 2:

[0334] An additional analysis was performed on further patients cohorts.

[0335] The studied groups are as follows:

[0336] Samples from healthy tissues

[0337] Fl: Patients with precancer with low precancer rate / year (associated with no recurrence) F2F3: Patients with precancer with high precancer rate / year (associated with recurrence) HP: Hyperplastic polyp (precancer)

[0338] SSL: Sessile Serrated Lesion (precancer)

[0339] LG or LG. AP: Low Grade Adenomatous Polyp (precancer)

[0340] HG or HG. AP: High Grade Adenomatous Polyp (precancer)

[0341] The following Tables show markers that are differentially expressed between samples from these specific groups.

[0342] For each comparison, differentially expressed markers are provided as a single list (“X list”) or, split between a list comprising only ncRNA without protein coding (“X-l list”) and a list comprising only protein coding markers (“X-2 list”).

[0343] The following marker lists are further provided:

[0344] List Al: Markers differentially expressed in Fl group as compared to (vs) F2F3 group List A2: Fl vs F2F3 List B: Precancer (HP+SSL+LG+HG) vs sain (UP in Precancer)

[0345] List CL Cancer vs sain (UP in cancer)

[0346] List C2: HG. AP vs sain

[0347] List C3: LG. AP vs sain

[0348] List C4: Cancer vs LG. AP

[0349] List C5: Cancer vs HG. AP

[0350] List C6: HG. AP vs LG. AP

[0351] List C7: HG. AP + LG. AP vs sain

[0352] List Overlap Al+B: gene UP in Precancer AND having significant association with precancer rate / year

[0353] List Overlap A2+B: gene UP in Precancer AND having significant association with precancer rate / year

[0354] lists overlap Cl, C2, C3

[0355] Lists overlap C4, C5, C6

[0356] lists overlap C2, C6

[0357] Intersection and combination

[0358] Table 44: List B of t-test Results for comparison between precancer vs healthy

[0359]

[0360] RNF43 1.50e-09 Up 125.4706(107.3441-143.5971) 48.9821(33.6021-64.3622) EPHX4 3.08e-09 Up 11.6723(9.3364-14.0082) 2.9286(1.4233-4.4339)

[0361] CCNO 3.25e-09 Up 19.8151(17.0598-22.5704) 8.625(6.3673-10.8827)

[0362] ITGA63.63e-09 Up 919.4202(810.1601-1028.6802) 439.5714(332.9796-546.1633) LINC020864.24e-09 Up 90.9076(81.485-100.3301) 43.875(32.3659-55.3841) SH3TC24.44e-09 Up 7.3025(6.2598-8.3452) 2.7321(1.7063-3.7579) LINC018074.79e-09 Up 2.2017(1.5874-2.816) 0.1786(-0.0063~0.3635)

[0363] PPM1H 7.97e-09 Up 22.4034(19.0674-25.7393) 9.4464(6.8221-12.0708) MSX2 8.42e-09 Up 28.3529(21.9687-34.7372) 6.1607(2.7048-9.6167) AC092894.1 9.08e-09 Up 22.5042(19.3636-25.6448) 10.0714(7.4551-12.6878) GAS6-AS1 9.54e-09 Up 17.9916(14.8478-21.1354) 6.875(5.0063-8.7437) KLRK1 1.23e-08 Up 4.563(3.6741-5.4519) 1.5(1.0102-1.9898)

[0364] LINC00858 1.28e-08 Up 3.4118(2.6469-4.1766) 0.75(0.307-1.193)

[0365] C2CD4A 1.31e-08 Up 28.7395(22.0592-35.4198) 6.375(3.1864-9.5636) LINC00668 1.43e-08 Up 142.5378(124.2591-160.8165) 62.8571(43.7612-81.953) OLFM4 1.50e-08 Up 4245.1765(3199.6902-5290.6627) 902.4286(550.5311-1254.326) LGR5 1.62e-08 Up 103.2605(83.4207-123.1003) 29.0536(14.035-44.0721) SOX9 1.66e-08 Up 329.9664(280.7245-379.2083) 142.9107(103.9979-181.8236) TNS4 1.76e-08 Up 45.1681(35.3293-55.0069) 12.9286(8.5717-17.2855)

[0366] LGR6 1.96e-08 Up 18.7059(15.4692-21.9426) 7.4464(5.4647-9.4282) LINC02163 1.96e-08 Up 1.7479(1.2901-2.2057) 0.25(0.0441-0.4559)

[0367] CYP4X1 2.09e-08 Up 34.9748(26.929-43.0206) 9.25(6.1931-12.3069)

[0368] MDFI 2.10e-08 Up 2.1849(1.809-2.5608) 0.7857(0.4981-1.0733)

[0369] AC124067.23.17e-08 Up 9.3866(8.0662-10.7069) 3.5357(2.0486-5.0228) CDH3 3.25e-08 Up 42.2269(34.9709-49.4829) 13.6964(7.143-20.2498) NANOS3 3.31e-08 Up 1.479(1.1692-1.7888) 0.4107(0.2144-0.607) AL590483.4 3.75e-08 Up 4.563(3.8121-5.314) 1.6607(1.0002-2.3212) LINC018195.17e-08 Up 19.4622(13.5322-25.3922) 1.8571(0.8598-2.8545) EPHB25.62e-08 Up 216.2437(190.9189-241.5685) 101.625(71.127-132.123) AC239800.26.26e-08 Up 5.2017(4.0578-6.3455) 1.4286(0.763-2.0941) LINC009206.76e-08 Up 10.2689(8.4686-12.0692) 3.8036(2.4074-5.1997) AC099792.1 7.06e-08 Up 2.5966(1.9348-3.2585) 0.5536(0.2837-0.8234) AC022101.1 7.17e-08 Up 12.1597(10.1157-14.2036) 5.0179(3.54-6.4957)

[0370] SP5 7.31e-08 Up 13.395(10.7245-16.0654) 4.4464(2.7574-6.1355) AC093866.1 8.30e-08 Up 12.0252(8.7363-15.3141) 1.9821(0.6958-3.2685) ALDH1L1 9.10e-08 Up 13.3782(11.3949-15.3614) 6.0179(4.3069-7.7288) LINC017489.60e-08 Up 11.5882(8.9459-14.2306) 3.2679(1.9416-4.5941) DLGAP1-AS2 1.12e-07 Up 14.563(12.4102-16.7158) 6.2321(4.1691-8.2952) C9orf50 1.12e-07 Up 4.7395(3.933-5.546) 1.75(1.0438-2.4562)

[0371] ENC1 1.32e-07 Up 214.2941(188.3784-240.2098) 103.0536(72.8579-133.2493) AC090371.2 1.46e-07 Up 1.2353(0.9311-1.5395) 0.2679(0.0947-0.441)

[0372] PF4 1.48e-07 Up 8.8908(6.8754-10.9061) 2.4821(1.3334-3.6309)

[0373] TDGF1P3 1.65e-07 Up 3.9664(3.2157-4.7171) 1.375(0.8028-1.9472)

[0374] HOXB6 1.81e-07 Up 125.7143(109.0249-142.4037) 59.0357(41.458-76.6134) SLC28A3 1.83e-07 Up 17.8235(14.0203-21.6268) 5.8393(3.6806-7.9979) GRIN2B 1.85e-07 Up 26.605(20.7381-32.4719) 6.75(2.4642-11.0358)

[0375] EPHB3 2.00e-07 Up 112.8487(95.479-130.2185) 49.25(33.7142-64.7858) LINC011242.07e-07 Up 2.0504(1.704-2.3968) 0.8214(0.5321-1.1108)

[0376] PLCB42.07e-07 Up 303.395(263.7183-343.0716) 152.3571(113.803-190.9113) OXGR1 2.12e-07 Up 9.9328(7.8528-12.0127) 3.5536(2.4886-4.6186) AC007608.22.13e-07 Up 1.2605(0.8754-1.6456) 0.1429(0.0134-0.2723) DUOX22.15e-07 Up 406.2017(295.5745-516.8289) 84.0179(45.1508-122.8849) KDELC1P1 2.20e-07 Up 1.9832(1.6295-2.3369) 0.6964(0.382-1.0109)

[0377] PCSK1 2.95e-07 Up 56.2857(39.7721-72.7993) 10.5714(8.1578-12.9851) ASCL2 3.11e-07 Up 157.2773(129.5923-184.9623) 55.9107(30.2152-81.6063) DBNDD1 3.15e-07 Up 2.395(1.9629-2.827) 0.9643(0.6496-1.2789)

[0378] L1TD1 3.56e-07 Up 216.4454(175.7899-257.1009) 66.4464(27.6952-105.1976) AC020891.23.62e-07 Up 1.1765(0.9359-1.4171) 0.375(0.194-0.556)

[0379] TEX454.75e-07 Up 4.5882(3.7773-5.3992) 1.7857(1.0973-2.4741)

[0380] EDAR 5.40e-07 Up 7.4202(5.9427-8.8977) 2.8929(2-3.7857) SERPINA1 5.93e-07 Up 445.9496(345.011-546.8882) 154.1786(107.5009-200.8563) C6orf223 6.46e-07 Up 8.437(6.647-10.227) 2.6786(1.3735-3.9837)

[0381] CD557.71e-07 Up 320.3025(249.6883-390.9168) 121.5357(92.2342-150.8373) LINC01357 8.52e-07 Up 2.3361(1.8493-2.8229) 0.75(0.3704-1.1296)

[0382] CEACAM6 8.72e-07 Up 948.3193(785.9949-1110.6437) 421.3036(295.5897-547.0174) ETV49.27e-07 Up 25.4958(18.9225-32.0691) 6.9286(3.9689-9.8882)

[0383] CLDN29.82e-07 Up 65.4622(50.4563-80.4681) 19.0893(8.8728-29.3058) SLCO1B3 1.05e-06 Up 18.4538(12.6431-24.2645) 2.8571(1.1973-4.517) LINC00853 1.12e-06 Up 1.7731(1.496-2.0502) 0.75(0.46-1.04)

[0384] AC104088.2 1.14e-06 Up 2.0924(1.7034-2.4815) 0.8214(0.5062-1.1367) AC016735.1 1.16e-06 Up 1.5714(1.2795-1.8633) 0.5893(0.3351-0.8435) AC124067.4 1.22e-06 Up 11.6387(9.8662-13.4111) 5.2321(3.4368-7.0275) AC091182.2 1.24e-06 Up 2.0168(1.5967-2.4369) 0.6964(0.3861-1.0067)

[0385] XKR9 1.31e-06 Up 10.8908(8.8852-12.8964) 4.4821(2.9214-6.0428)

[0386] PRSS22 1.41e-06 Up 24.5546(18.9682-30.141) 8.5893(5.6112-11.5674) LINC01301 1.62e-06 Up 4.5966(3.6589-5.5344) 1.8036(1.1963-2.4109) SLCO4A1-AS1 1.71e-06 Up 4.6134(3.6304-5.5965) 1.6964(1.0629-2.33) AC079160.1 1.78e-06 Up 7.605(6.2616-8.9485) 3.3393(2.2738-4.4047)

[0387] GATA2-AS1 2.07e-06 Up 6.9664(5.485-8.4478) 2.375(1.2532-3.4968)

[0388] MYEOV 2.13e-06 Up 19.2017(14.7966-23.6068) 6.6429(4.1134-9.1724) RPL10P22.22e-06 Up 0.8403(0.644-1.0366) 0.25(0.1125-0.3875)

[0389] LINC025772.25e-06 Up 1.042(0.7058-1.3782) 0.1607(0.0491-0.2723)

[0390] C17orf772.39e-06 Up 4.9244(3.8085-6.0402) 1.1964(0.1694-2.2234) ARHGEF38-IT1 2.47e-06 Up 2.2605(1.8448-2.6763) 0.9286(0.579-1.2781) KLK102.50e-06 Up 17.1933(12.2415-22.145) 4.0893(2.1845-5.9941)

[0391] TDGF1 2.68e-06 Up 18.7899(15.0547-22.5252) 7.2143(4.2951-10.1335)

[0392] C2CD4B 3.00e-06 Up 21.5966(17.4178-25.7755) 9.3036(6.4507-12.1565) LINC002393.13e-06 Up 1.8992(1.5041-2.2942) 0.75(0.4884-1.0116)

[0393] GDF15 3.51e-06 Up 115.5462(82.8172-148.2752) 32.1786(22.3441-42.0131) CPNE7 3.55e-06 Up 7.8824(6.1136-9.6511) 2.8036(1.66-3.9471)

[0394] RETNLB 3.56e-06 Up 291.6807(221.3911-361.9702) 99.2321(61.8005-136.6638) LINC022543.56e-06 Up 6.395(4.5047-8.2852) 1.2679(0.3077-2.228)

[0395] WDR723.63e-06 Up 13.8824(10.2857-17.479) 4.4464(2.9576-5.9352) TMEM211 4.49e-06 Up 3.2101(2.5175-3.9027) 1.1071(0.5603-1.654)

[0396] C4BPB 4.84e-06 Up 27.5294(23.1546-31.9043) 12.6786(8.2345-17.1227)

[0397] FEZF1-AS1 5.24e-06 Up 6.6723(4.722-8.6226) 1.5357(0.6025-2.469)

[0398] REG4 5.94e-06 Up 1718.563(1265.1595-2171.9666) 414.3393(94.5524-734.1262) TLX1 6.45e-06 Up 4.2521(3.1078-5.3964) 1.3571(0.9136-1.8007)

[0399] AP005233.26.62e-06 Up 10.7227(8.6393-12.806) 4.4464(2.7535-6.1393) AC106045.1 7.10e-06 Up 3.2353(2.6479-3.8227) 1.2679(0.6647-1.871)

[0400] LRRC367.13e-06 Up 4.437(3.5233-5.3507) 1.8393(1.1999-2.4787)

[0401] VPS9D1-AS1 7.24e-06 Up 3.3529(2.6973-4.0086) 1.25(0.6303-1.8697) AC018629.1 7.72e-06 Up 8.1429(6.2569-10.0288) 3.1964(2.2162-4.1766) SLC35D3 9.41e-06 Up 2.2605(1.5093-3.0118) 0.4643(0.2876-0.6409) LINC016599.49e-06 Up 4.6134(3.58-5.6469) 1.8929(1.3181-2.4676)

[0402] CARMIL3 1.00e-05 Up 3.0336(2.5235-3.5438) 1.375(0.8629-1.8871) AC027808.2 1.08e-05 Up 1.605(1.2441-1.966) 0.5(0.177-0.823)

[0403] FIRRE 1.11e-05 Up 5.1933(3.893-6.4936) 1.9643(1.4215-2.5071)

[0404] FSIP2-AS2 1.13e-05 Up 3.6723(3.0398-4.3047) 1.625(0.9881-2.2619)

[0405] AP005271.1 1.18e-05 Up 1.084(0.7638-1.4042) 0.25(0.0713-0.4287) AC002057.2 1.19e-05 Up 1.3613(1.0489-1.6737) 0.4464(0.1915-0.7014) AP000619.1 1.21e-05 Up 1.0168(0.7569-1.2768) 0.3214(0.1591-0.4838)

[0406] MSX1 1.24e-05 Up 29.7563(21.1247-38.3879) 8.7143(5.4705-11.9581)

[0407] TFAP2A-AS1 1.32e-05 Up 1.3613(0.9783-1.7444) 0.3571(0.132-0.5822)

[0408] ULBP3 1.34e-05 Up 7.0504(5.4862-8.6147) 3(2.1244-3.8756)

[0409] CCDC33 1.35e-05 Up 0.9916(0.6732-1.31) 0.1964(0.0482-0.3446)

[0410] CLCA1 1.36e-05 Up 3212.2521(2513.9564-3910.5478) 1392.3929(989.2431-1795.5426) ART3 1.45e-05 Up 13.563(9.4525-17.6736) 3.7143(2.2956-5.1329)

[0411] FZD9 1.50e-05 Up 2.1765(1.5329-2.8201) 0.6429(0.4297-0.8561)

[0412] AC104088.3 1.61e-05 Up 3.5294(2.7407-4.3182) 1.3571(0.7875-1.9268) AL354953.1 1.75e-05 Up 3.6303(2.8981-4.3625) 1.5357(0.9424-2.129) CYP4A22-AS1 1.91e-05 Up 1.1429(0.9086-1.3772) 0.4464(0.2364-0.6565) AC007608.4 1.94e-05 Up 56.7983(42.172-71.4247) 17.4107(7.2275-27.5939) AL 133297.22.13e-05 Up 1.916(1.4177-2.4143) 0.6607(0.3844-0.937) KLK122.27e-05 Up 6.5714(4.5525-8.5903) 1.7143(0.8272-2.6013)

[0413] PKD1L3 2.33e-05 Up 0.9664(0.661-1.2717) 0.2321(0.0971-0.3672)

[0414] DLX6-AS1 2.42e-05 Up 4.6303(3.135-6.1255) 1.1071(0.5301-1.6842) AC005307.1 2.58e-05 Up 2.1597(1.4362-2.8831) 0.4643(0.1894-0.7391)

[0415] IFI62.58e-05 Up 197.6134(144.0323-251.1946) 71.7679(51.0182-92.5175) CXCL3 2.84e-05 Up 182.2773(142.271-222.2837) 63.0357(25.1988-100.8727) AC007608.1 2.93e-05 Up 8.5462(6.2067-10.8858) 2.6964(1.3396-4.0533) SCARNA223.03e-05 Up 15.6639(11.9354-19.3923) 6.375(4.2274-8.5226) SETD6P1 3.14e-05 Up 1.3613(1.0507-1.672) 0.5179(0.2784-0.7573)

[0416] GJB3 3.50e-05 Up 23.7311(19.7019-27.7603) 11.0536(6.7262-15.3809) DMRTA24.28e-05 Up 2.9328(1.9729-3.8927) 0.6071(0.0723-1.142) CCDC604.99e-05 Up 3.7731(2.9228-4.6234) 1.625(1.0505-2.1995)

[0417] NXF3 5.63e-05 Up 8.2101(5.8522-10.568) 2.3214(0.7498-3.893)

[0418] RNU1-30P 7.25e-05 Up 1.5126(1.201-1.8242) 0.6071(0.2937-0.9206) SERPINB57.64e-05 Up 96.8403(74.1115-119.5691) 31.5357(9.0216-54.0498) LINC01411 7.87e-05 Up 3.5546(2.1655-4.9437) 0.6071(0.2545-0.9598) PNPLA3 8.05e-05 Up 5.8067(4.3677-7.2457) 2.2321(1.2198-3.2445)

[0419] PI3 8.09e-05 Up 92.9916(63.0363-122.9469) 26.875(14.6211-39.1289) LINC02253 8.71e-05 Up 3.1429(2.1282-4.1575) 0.6071 (-0.1306-1.3449) AL354743.2 8.89e-05 Up 0.9916(0.6391-1.3441) 0.1964(0.0239-0.369) DLX69.11e-05 Up 2.3697(1.5677-3.1718) 0.5893(0.229-0.9496)

[0420] CHST49.29e-05 Up 1.5714(0.9672-2.1756) 0.2857(0.0966-0.4748) SLC22A11 9.57e-05 Up 3.9748(2.839-5.1105) 1.1964(0.4079-1.985) AC036176.3 1.1 le-04 Up 4.3277(3.29-5.3655) 1.6429(0.7801-2.5056) C2orf70 l.lle-04 Up 3.7143(3.0005-4.4281) 1.6964(0.978-2.4149) ZDHHC8P1 1.33e-04 Up 26.3697(21.4688-31.2707) 12.7679(7.8944-17.6413) AC090116.1 1.41e-04 Up 2.6891(2.0022-3.376) 0.8929(0.285-1.5007) MUC2 1.46e-04 Up 1470.0168(1228.3958-1711.6379) 727.3036(436.0641-1018.543) AC078993.1 1.47e-04 Up 15.8403(10.2115-21.4692) 3.9107(1.625-6.1964) NKD1 1.49e-04 Up 100.6218(72.993-128.2507) 35.3929(16.5911-54.1946) SPINK 4 1.51e-04 Up 847.3529(689.3787-1005.3272) 389.4821(216.4551-562.5092) CUBNP3 1.62e-04 Up 0.6975(0.4456-0.9493) 0.1607(0.0491-0.2723) AL359075.1 1.68e-04 Up 1.0756(0.6944-1.4568) 0.2679(0.1024-0.4333) REG1B 1.74e-04 Up 203.7899(107.4149-300.1649) 12.8036(-3.3621-28.9692) CASC9 1.92e-04 Up 22.5714(18.7878-26.3551) 11.5179(7.1915-15.8442) CCL202.15e-04 Up 134.5462(99.3866-169.7058) 52.9643(28.3929-77.5356) AC144450.1 2.44e-04 Up 1.0084(0.7364-1.2804) 0.3571(0.1439-0.5703) LINC01833 2.52e-04 Up 4.4202(3.0428-5.7975) 1.5357(0.8719-2.1995) CLIC3 2.90e-04 Up 5.8824(4.565-7.1997) 2.7679(1.7351-3.8006)

[0421] S100P 2.91e-04 Up 746.8487(614.9954-878.702) 360.3571(200.8299-519.8844) SLC6A143.02e-04 Up 42.2857(26.3574-58.214) 10.9464(5.7194-16.1734) HS6ST23.22e-04 Up 6.437(4.5877-8.2862) 2.3571(1.1493-3.565)

[0422] SDR16C5 3.26e-04 Up 59.6807(48.6996-70.6618) 30.0357(18.3415-41.7299) FOXD1 3.26e-04 Up 1.958(1.2611-2.6548) 0.5536(0.2561-0.851) AL589669.1 3.41e-04 Up 5.7395(4.3244-7.1546) 2.5536(1.553-3.5542) AC010547.2 3.50e-04 Up 0.8992(0.5366-1.2618) 0.1786(0.0332-0.324) AC010378.2 3.65e-04 Up 1.1597(0.7483-1.571) 0.3214(0.1229-0.5199) KCTD164.13e-04 Up 9.6891(6.0588-13.3194) 2.4643(0.8543-4.0743)

[0423] EVX1 4.19e-04 Up 2.6639(1.7906-3.5371) 0.8571(0.3769-1.3374)

[0424] LCN24.28e-04 Up 943.0336(525.1126-1360.9546) 161.3036(67.3015-255.3057) LINC015554.31e-04 Up 1.1513(0.8293-1.4733) 0.4107(0.1565-0.6649) CBX24.76e-04 Up 3.4034(2.2015-4.6053) 1.1071(0.687-1.5273) AC124067.3 4.91e-04 Up 8.1261(6.737-9.5151) 3.8571(1.9318-5.7825) AL606537.1 6.07e-04 Up 3.605(2.9079-4.3022) 1.75(0.9601-2.5399)

[0425] GRM86.10e-04 Up 6.1849(5.0473-7.3225) 3.1786(1.9038-4.4533)

[0426] XACT 6.22e-04 Up 4.3613(3.3858-5.3368) 2.1429(1.3363~2.9494) LINC024186.27e-04 Up 6.3782(3.8895-8.8668) 1.5536(0.3993-2.7079) MMP77.65e-04 Up 39.7227(26.7145-52.7309) 12.4821(3.505-21.4593) NOS27.92e-04 Up 41.916(32.0405-51.7914) 17.5(7.2993-27.7007) AL445490.1 8.52e-04 Up 1.479(1.0136-1.9444) 0.5(0.1651-0.8349) LY6G6F-LY6G6D 8.70e-04 Up 26.3445(15.2665-37.4226) 6.3571(2.7688-9.9455) AL121761.1 8.83e-04 Up 3.8319(2.0603-5.6035) 0.7143(0.323-1.1056) LINC019960.001 Up 3.0924(2.1683-4.0166) 1.2321(0.6258-1.8385) NPSR1-AS1 0.001 Up 3.6555(2.4196-4.8913) 0.9821(-0.0257~l.99) AP000344.1 0.001 Up 1.3613(1-1.7227) 0.5714(0.2656-0.8772)

[0427] ZIC20.001 Up 17.084(10.0708-24.0973) 3.8929(0.2356-7.5501)

[0428] CNTD20.001 Up 4.0336(2.6431-5.4242) 1.2321(0.2822-2.182)

[0429] SOX1 0.001 Up 2.3782(1.206-3.5503) 0.3571(0.0754-0.6388)

[0430] FIBCD1 0.001 Up 14.3782(9.3139-19.4424) 5.0893(2.7584-7.4202)

[0431] OTX1 0.001 Up 1.916(1.275-2.5569) 0.6071(0.1428-1.0715)

[0432] TNFSF90.001 Up 6.5798(3.7005-9.4592) 1.6429(0.9475-2.3383)

[0433] MMP12 0.001 Up 93.9664(55.0754-132.8574) 27.7143(18.8073-36.6213) AC005833.1 0.001 Up 12.2857(9.4992-15.0723) 6.0714(3.4766-8.6663) RAET1L 0.002 Up 2.6555(1.5695-3.7414) 0.6964(0.1758-1.217)

[0434] PLA2G30.002 Up 1.8403(1.2397-2.441) 0.6071(0.1235-1.0907)

[0435] MUC170.002 Up 64.9328(42.6071-87.2584) 26.6607(17.702-35.6195) AC007493.1 0.002 Up 2.1008(1.336-2.8657) 0.5357(-0.0917~1.1632) APCDD1 0.002 Up 135.605(99.0953-172.1148) 65.4643(40.1012-90.8273) PRKCG 0.002 Up 1.7479(1.1448-2.351) 0.7143(0.4656-0.963) AC093817.2 0.002 Up 1.0588(0.6165-1.5011) 0.2679(0.0311-0.5046) ZNF736P9Y 0.002 Up 1.5546(1.0221-2.0871) 0.5714(0.245-0.8979) HTR1D 0.002 Up 8.8403(5.4859-12.1948) 2.7857(0.8992-4.6723) LINC01594 0.002 Up 2.2269(1.6739-2.7798) 1(0.4406-1.5594)

[0436] CASC80.002 Up 2.9412(2.1099-3.7725) 1.1607(0.3749-1.9465) AC004009.20.002 Up 1.7059(0.9367-2.4751) 0.4643(0.2667-0.6618) NOTUM 0.002 Up 21.2857(12.0172-30.5543) 5.4643(1.1816-9.747)

[0437] NPW 0.003 Up 5.7815(4.0065-7.5566) 2.4643(1.2451-3.6835)

[0438] GJB40.003 Up 2.1429(1.6612-2.6245) 0.8214(0.1136-1.5292) AC053545.1 0.003 Up 1.9664(1.4369-2.4959) 0.8571(0.3609-1.3534) TBX180.003 Up 4.4034(2.8236-5.9831) 1.7143(0.8633-2.5653)

[0439] NAT80.003 Up 2.9916(1.6723-4.3109) 0.9107(0.4826-1.3388)

[0440] ZIC50.004 Up 4.5882(2.4431-6.7333) 1.0536(0.0215-2.0856)

[0441] SNRPEP40.004 Up 3.3361(2.3163-4.356) 1.4107(0.5688-2.2526)

[0442] BBOX1-AS1 0.004 Up 2.1176(1.2901-2.9452) 0.75(0.3012-1.1988) ELFN1-AS1 0.005 Up 3.2689(2.2677-4.2701) 1.4643(0.7155-2.213)

[0443] REN 0.005 Up 2.4706(1.3068-3.6344) 0.6429(0.1414-1.1443)

[0444] AL109615.3 0.005 Up 2.9832(1.3457-4.6207) 0.5893(0.2838-0.8947) FEZF1 0.005 Up 2.3025(0.9298-3.6752) 0.3036(0.0538-0.5533)

[0445] NP SRI 0.006 Up 2.5798(1.6822-3.4774) 0.7857(-0.1245-1.696)

[0446] RPL21P1190.006 Up 13.1765(5.8113-20.5417) 2.75(2.1739-3.3261) AL669983.1 0.007 Up 75.7311(51.3812-100.081) 38.3571(25.8871-50.8271) IGLV6-570.008 Up 3.4034(2.1592-4.6475) 1.4107(0.602-2.2194)

[0447] DCDC20.009 Up 6.916(5.0819-8.75) 3.7321(2.2091-5.2552)

[0448] REG1A 0.010 Up 1433.5714(810.6429-2056.5) 484.5357(112.8535-856.218) CXCL1 0.010 Up 217.5042(117.1754-317.833) 71.6429(22.9354-120.3504) CXCL11 0.011 Up 18.8992(13.8281-23.9702) 7.0893(-0.4717~14.6503) GJB50.013 Up 5.7899(3.8429-7.7369) 2.2143(0.1756-4.253)

[0449] SNORD3A 0.013 Up 69.6975(28.5796-110.8154) 15.25(3.7409-26.7591) LINC005200.014 Up 8.3109(4.9566-11.6653) 3.5714(1.7915-5.3514) MTATP8P20.015 Up 27.1849(15.768-38.6018) 10.0714(2.2838-17.859) LEMD1 0.017 Up 1.563(0.553-2.5731) 0.2857(0.0121-0.5594)

[0450] AFAP1-AS1 0.018 Up 1.916(0.7881-3.0438) 0.5179(0.2429-0.7928) LCN150.020 Up 16.4286(8.945-23.9122) 5.7857(0.7929-10.7785)

[0451] CABP70.021 Up 1.2269(0.5934-1.8604) 0.4286(0.1898-0.6673)

[0452] RN7SL3 0.021 Up 2.0672(1.1862-2.9483) 0.9107(0.4647-1.3567)

[0453] SLC5A80.025 Up 2.4286(1.5766-3.2805) 1.3214(0.8587-1.7842)

[0454]

[0455] Table 45: List B-l of t-test Results for comparison between precancer vs healthy (only with ncRNA without protein coding)

[0456]

[0457] AC016735.1 1.16e-06 Up 1.5714(1.2795-1.8633) 0.5893(0.3351-0.8435) AC124067.41.22e-06 Up 11.6387(9.8662-13.4111) 5.2321(3.4368-7.0275) AC091182.21.24e-06 Up 2.0168(1.5967-2.4369) 0.6964(0.3861-1.0067) LINC01301 1.62e-06 Up 4.5966(3.6589-5.5344) 1.8036(1.1963-2.4109) SLCO4A1-AS1 1.71e-06 Up 4.6134(3.6304-5.5965) 1.6964(1.0629-2.33) AC079160.1 1.78e-06 Up 7.605(6.2616-8.9485) 3.3393(2.2738-4.4047) GATA2-AS1 2.07e-06 Up 6.9664(5.485-8.4478) 2.375(1.2532-3.4968) RPL10P22.22e-06 Up 0.8403(0.644-1.0366) 0.25(0.1125-0.3875) LINC025772.25e-06 Up 1.042(0.7058-1.3782) 0.1607(0.0491-0.2723) ARHGEF38-IT1 2.47e-06 Up 2.2605(1.8448-2.6763) 0.9286(0.579-1.2781) LINC022543.56e-06 Up 6.395(4.5047-8.2852) 1.2679(0.3077-2.228) FEZF1-AS15.24e-06 Up 6.6723(4.722-8.6226) 1.5357(0.6025-2.469) AP005233.26.62e-06 Up 10.7227(8.6393-12.806) 4.4464(2.7535-6.1393) AC106045.1 7.10e-06 Up 3.2353(2.6479-3.8227) 1.2679(0.6647-1.871) VPS9D1-AS1 7.24e-06 Up 3.3529(2.6973-4.0086) 1.25(0.6303-1.8697) AC018629.1 7.72e-06 Up 8.1429(6.2569-10.0288) 3.1964(2.2162-4.1766) LINC016599.49e-06 Up 4.6134(3.58-5.6469) 1.8929(1.3181-2.4676) FIRRE 1.11e-05 Up 5.1933(3.893-6.4936) 1.9643(1.4215-2.5071) FSIP2-AS21.13e-05 Up 3.6723(3.0398-4.3047) 1.625(0.9881-2.2619) AP005271.1 1.18e-05 Up 1.084(0.7638-1.4042) 0.25(0.0713-0.4287) AC002057.21.19e-05 Up 1.3613(1.0489-1.6737) 0.4464(0.1915-0.7014) AP000619.1 1.21e-05 Up 1.0168(0.7569-1.2768) 0.3214(0.1591-0.4838) TFAP2A-AS1 1.32e-05 Up 1.3613(0.9783-1.7444) 0.3571(0.132-0.5822) AC104088.31.61e-05 Up 3.5294(2.7407-4.3182) 1.3571(0.7875-1.9268) AL354953.1 1.75e-05 Up 3.6303(2.8981-4.3625) 1.5357(0.9424-2.129) CYP4A22-AS1 1.91e-05 Up 1.1429(0.9086-1.3772) 0.4464(0.2364-0.6565) AC007608.41.94e-05 Up 56.7983(42.172-71.4247) 17.4107(7.2275-27.5939) AL133297.22.13e-05 Up 1.916(1.4177-2.4143) 0.6607(0.3844-0.937) DLX6-AS1 2.42e-05 Up 4.6303(3.135-6.1255) 1.1071(0.5301-1.6842) AC005307.1 2.58e-05 Up 2.1597(1.4362-2.8831) 0.4643(0.1894-0.7391) AC007608.1 2.93e-05 Up 8.5462(6.2067-10.8858) 2.6964(1.3396-4.0533) SCARNA223.03e-05 Up 15.6639(11.9354-19.3923) 6.375(4.2274-8.5226) SETD6P1 3.14e-05 Up 1.3613(1.0507-1.672) 0.5179(0.2784-0.7573) RNU1 -30P 7.25e-05 Up 1.5126(1.201-1.8242) 0.6071 (0.2937-0.9206) LINC01411 7.87e-05 Up 3.5546(2.1655-4.9437) 0.6071(0.2545-0.9598) LINC02253 8.71e-05 Up 3.1429(2.1282-4.1575) 0.6071(-0.1306-1.3449) AL354743.28.89e-05 Up 0.9916(0.6391-1.3441) 0.1964(0.0239-0.369) AC036176.3 1.1 le-04 Up 4.3277(3.29-5.3655) 1.6429(0.7801-2.5056) ZDHHC8P1 1.33e-04 Up 26.3697(21.4688-31.2707) 12.7679(7.8944-17.6413) AC090116.1 1.41e-04 Up 2.6891(2.0022-3.376) 0.8929(0.285-1.5007) AC078993.1 1.47e-04 Up 15.8403(10.2115-21.4692) 3.9107(1.625-6.1964) CUBNP3 1.62e-04 Up 0.6975(0.4456-0.9493) 0.1607(0.0491-0.2723) AL359075.1 1.68e-04 Up 1.0756(0.6944-1.4568) 0.2679(0.1024-0.4333) CASC9 1.92e-04 Up 22.5714(18.7878-26.3551) 11.5179(7.1915-15.8442) AC144450.1 2.44e-04 Up 1.0084(0.7364-1.2804) 0.3571(0.1439-0.5703) LINC018332.52e-04 Up 4.4202(3.0428-5.7975) 1.5357(0.8719-2.1995) AL589669.1 3.41e-04 Up 5.7395(4.3244-7.1546) 2.5536(1.553-3.5542) AC010547.23.50e-04 Up 0.8992(0.5366-1.2618) 0.1786(0.0332-0.324) AC010378.23.65e-04 Up 1.1597(0.7483-1.571) 0.3214(0.1229-0.5199) AC124067.34.91e-04 Up 8.1261(6.737-9.5151) 3.8571(1.9318-5.7825) AL606537.1 6.07e-04 Up 3.605(2.9079-4.3022) 1.75(0.9601-2.5399) XACT 6.22e-04 Up 4.3613(3.3858-5.3368) 2.1429(1.3363-2.9494) LINC024186.27e-04 Up 6.3782(3.8895-8.8668) 1.5536(0.3993-2.7079) AL445490.1 8.52e-04 Up 1.479(1.0136-1.9444) 0.5(0.1651-0.8349) LINC019960.001 Up 3.0924(2.1683-4.0166) 1.2321(0.6258-1.8385) NPSR1-AS1 0.001 Up 3.6555(2.4196-4.8913) 0.9821(-0.0257~1.99) AP000344.1 0.001 Up 1.3613(1-1.7227) 0.5714(0.2656-0.8772) AC007493.1 0.002 Up 2.1008(1.336-2.8657) 0.5357(-0.0917~1.1632) AC093817.2 0.002 Up 1.0588(0.6165-1.5011) 0.2679(0.0311-0.5046) ZNF736P9Y 0.002 Up 1.5546(1.0221-2.0871) 0.5714(0.245-0.8979)

[0458]

[0459] Table 46: List B-2 of t-test Results for comparison between precancer vs healthy (only with protein coding)

[0460]

[0461] SH3TC24.44e-09 Up 7.3025(6.2598-8.3452) 2.7321(1.7063-3.7579)

[0462] PPM1H 7.97e-09 Up 22.4034(19.0674-25.7393) 9.4464(6.8221-12.0708) MSX28.42e-09 Up 28.3529(21.9687-34.7372) 6.1607(2.7048-9.6167)

[0463] KLRK1 1.23e-08 Up 4.563(3.6741-5.4519) 1.5(1.0102-1.9898)

[0464] C2CD4A 1.31e-08 Up 28.7395(22.0592-35.4198) 6.375(3.1864-9.5636) OLFM4 1.50e-08 Up 4245.1765(3199.6902-5290.6627) 902.4286(550.5311-1254.326) LGR51.62e-08 Up 103.2605(83.4207-123.1003) 29.0536(14.035-44.0721) SOX91.66e-08 Up 329.9664(280.7245-379.2083) 142.9107(103.9979-181.8236) TNS41.76e-08 Up 45.1681(35.3293-55.0069) 12.9286(8.5717-17.2855)

[0465] LGR61.96e-08 Up 18.7059(15.4692-21.9426) 7.4464(5.4647-9.4282)

[0466] CYP4X1 2.09e-08 Up 34.9748(26.929-43.0206) 9.25(6.1931-12.3069)

[0467] MDFI 2.10e-08 Up 2.1849(1.809-2.5608) 0.7857(0.4981-1.0733)

[0468] CDH33.25e-08 Up 42.2269(34.9709-49.4829) 13.6964(7.143-20.2498) NANOS33.31e-08 Up 1.479(1.1692-1.7888) 0.4107(0.2144-0.607)

[0469] EPHB25.62e-08 Up 216.2437(190.9189-241.5685) 101.625(71.127-132.123) SP5 7.31e-08 Up 13.395(10.7245-16.0654) 4.4464(2.7574-6.1355)

[0470] ALDH1L1 9.10e-08 Up 13.3782(11.3949-15.3614) 6.0179(4.3069-7.7288) C9orf501.12e-07 Up 4.7395(3.933-5.546) 1.75(1.0438-2.4562)

[0471] ENC1 1.32e-07 Up 214.2941(188.3784-240.2098) 103.0536(72.8579-133.2493) PF41.48e-07 Up 8.8908(6.8754-10.9061) 2.4821(1.3334-3.6309)

[0472] HOXB61.81e-07 Up 125.7143(109.0249-142.4037) 59.0357(41.458-76.6134) SLC28A3 1.83e-07 Up 17.8235(14.0203-21.6268) 5.8393(3.6806-7.9979) GRIN2B 1.85e-07 Up 26.605(20.7381-32.4719) 6.75(2.4642-11.0358)

[0473] EPHB32.00e-07 Up 112.8487(95.479-130.2185) 49.25(33.7142-64.7858) LINC011242.07e-07 Up 2.0504(1.704-2.3968) 0.8214(0.5321-1.1108)

[0474] PLCB42.07e-07 Up 303.395(263.7183-343.0716) 152.3571(113.803-190.9113) OXGR1 2.12e-07 Up 9.9328(7.8528-12.0127) 3.5536(2.4886-4.6186)

[0475] DUOX22.15e-07 Up 406.2017(295.5745-516.8289) 84.0179(45.1508-122.8849) PCSK1 2.95e-07 Up 56.2857(39.7721-72.7993) 10.5714(8.1578-12.9851) ASCL23.11e-07 Up 157.2773(129.5923-184.9623) 55.9107(30.2152-81.6063) DBNDD1 3.15e-07 Up 2.395(1.9629-2.827) 0.9643(0.6496-1.2789)

[0476] L1TD1 3.56e-07 Up 216.4454(175.7899-257.1009) 66.4464(27.6952-105.1976) TEX454.75e-07 Up 4.5882(3.7773-5.3992) 1.7857(1.0973-2.4741)

[0477] ED AR 5.40e-07 Up 7.4202(5.9427-8.8977) 2.8929(2-3.7857)

[0478] SERPINA1 5.93e-07 Up 445.9496(345.011-546.8882) 154.1786(107.5009-200.8563) C6orf2236.46e-07 Up 8.437(6.647-10.227) 2.6786(1.3735-3.9837)

[0479] CD55 7.71e-07 Up 320.3025(249.6883-390.9168) 121.5357(92.2342-150.8373) CEACAM68.72e-07 Up 948.3193(785.9949-1110.6437) 421.3036(295.5897-547.0174) ETV49.27 e-07 Up 25.4958(18.9225-32.0691) 6.9286(3.9689-9.8882)

[0480] CLDN29.82e-07 Up 65.4622(50.4563-80.4681) 19.0893(8.8728-29.3058) SLCO1B3 1.05e-06 Up 18.4538(12.6431-24.2645) 2.8571(1.1973-4.517)

[0481] XKR91.31e-06 Up 10.8908(8.8852-12.8964) 4.4821(2.9214-6.0428)

[0482] PRSS221.41e-06 Up 24.5546(18.9682-30.141) 8.5893(5.6112-11.5674) MYEOV 2.13e-06 Up 19.2017(14.7966-23.6068) 6.6429(4.1134-9.1724) C17orf772.39e-06 Up 4.9244(3.8085-6.0402) 1.1964(0.1694-2.2234)

[0483] KLK102.50e-06 Up 17.1933(12.2415-22.145) 4.0893(2.1845-5.9941)

[0484] TDGF1 2.68e-06 Up 18.7899(15.0547-22.5252) 7.2143(4.2951-10.1335) C2CD4B 3.00e-06 Up 21.5966(17.4178-25.7755) 9.3036(6.4507-12.1565) LINC002393.13e-06 Up 1.8992(1.5041-2.2942) 0.75(0.4884-1.0116)

[0485] GDF153.51e-06 Up 115.5462(82.8172-148.2752) 32.1786(22.3441-42.0131) CPNE73.55e-06 Up 7.8824(6.1136-9.6511) 2.8036(1.66-3.9471)

[0486] RETNLB 3.56e-06 Up 291.6807(221.3911-361.9702) 99.2321(61.8005-136.6638) WDR723.63e-06 Up 13.8824(10.2857-17.479) 4.4464(2.9576-5.9352) TMEM211 4.49e-06 Up 3.2101(2.5175-3.9027) 1.1071(0.5603-1.654)

[0487] C4BPB 4.84e-06 Up 27.5294(23.1546-31.9043) 12.6786(8.2345-17.1227) REG45.94e-06 Up 1718.563(1265.1595-2171.9666) 414.3393(94.5524-734.1262) TLX1 6.45e-06 Up 4.2521(3.1078-5.3964) 1.3571(0.9136-1.8007)

[0488] LRRC367.13e-06 Up 4.437(3.5233-5.3507) 1.8393(1.1999-2.4787)

[0489] SLC35D39.41e-06 Up 2.2605(1.5093-3.0118) 0.4643(0.2876-0.6409) CARMIL3 1.00e-05 Up 3.0336(2.5235-3.5438) 1.375(0.8629-1.8871) AC027808.21.08e-05 Up 1.605(1.2441-1.966) 0.5(0.177-0.823)

[0490] MSX1 1.24e-05 Up 29.7563(21.1247-38.3879) 8.7143(5.4705-11.9581)

[0491] ULBP3 1.34e-05 Up 7.0504(5.4862-8.6147) 3(2.1244-3.8756)

[0492] CCDC33 1.35e-05 Up 0.9916(0.6732-1.31) 0.1964(0.0482-0.3446)

[0493] CLCA1 1.36e-05 Up 3212.2521(2513.9564-3910.5478) 1392.3929(989.2431-1795.5426) ART3 1.45e-05 Up 13.563(9.4525-17.6736) 3.7143(2.2956-5.1329)

[0494] FZD91.50e-05 Up 2.1765(1.5329-2.8201) 0.6429(0.4297-0.8561)

[0495] KLK122.27e-05 Up 6.5714(4.5525-8.5903) 1.7143(0.8272-2.6013)

[0496] PKD1L32.33e-05 Up 0.9664(0.661-1.2717) 0.2321(0.0971-0.3672)

[0497] IFI62.58e-05 Up 197.6134(144.0323-251.1946) 71.7679(51.0182-92.5175) CXCL32.84e-05 Up 182.2773(142.271-222.2837) 63.0357(25.1988-100.8727) GJB33.50e-05 Up 23.7311(19.7019-27.7603) 11.0536(6.7262-15.3809) DMRTA24.28e-05 Up 2.9328(1.9729-3.8927) 0.6071(0.0723-1.142)

[0498] CCDC604.99e-05 Up 3.7731(2.9228-4.6234) 1.625(1.0505-2.1995)

[0499] 0NXF35.63e-05 Up 8.2101(5.8522-10.568) 2.3214(0.7498-3.893)

[0500] 1 SERPINB5 7.64e-05 Up 96.8403(74.1115-119.5691) 31.5357(9.0216-54.0498) PNPLA38.05e-05 Up 5.8067(4.3677-7.2457) 2.2321(1.2198-3.2445)

[0501] PI38.09e-05 Up 92.9916(63.0363-122.9469) 26.875(14.6211-39.1289)

[0502] DLX69.1 le-05 Up 2.3697(1.5677-3.1718) 0.5893(0.229-0.9496)

[0503] CHST49.29e-05 Up 1.5714(0.9672-2.1756) 0.2857(0.0966-0.4748)

[0504] SLC22A11 9.57e-05 Up 3.9748(2.839-5.1105) 1.1964(0.4079-1.985)

[0505] 7 C2orf70 l.lle-04 Up 3.7143(3.0005-4.4281) 1.6964(0.978-2.4149)

[0506] MUC2 1.46e-04 Up 1470.0168(1228.3958-1711.6379) 727.3036(436.0641-1018.543) NKD1 1.49e-04 Up 100.6218(72.993-128.2507) 35.3929(16.5911-54.1946) 0SPINK4 1.51e-04 Up 847.3529(689.3787-1005.3272) 389.4821(216.4551-562.5092) 1 REG1B 1.74e-04 Up 203.7899(107.4149-300.1649) 12.8036(-3.3621~28.9692) CCL202.15e-04 Up 134.5462(99.3866-169.7058) 52.9643(28.3929-77.5356) CLIC32.90e-04 Up 5.8824(4.565-7.1997) 2.7679(1.7351-3.8006)

[0507] S100P 2.91e-04 Up 746.8487(614.9954-878.702) 360.3571(200.8299-519.8844) SLC6A143.02e-04 Up 42.2857(26.3574-58.214) 10.9464(5.7194-16.1734) HS6ST23.22e-04 Up 6.437(4.5877-8.2862) 2.3571(1.1493-3.565)

[0508] 7SDR16C53.26e-04 Up 59.6807(48.6996-70.6618) 30.0357(18.3415-41.7299) FOXD1 3.26e-04 Up 1.958(1.2611-2.6548) 0.5536(0.2561-0.851)

[0509] KCTD164.13e-04 Up 9.6891(6.0588-13.3194) 2.4643(0.8543-4.0743)

[0510] 0EVX1 4.19e-04 Up 2.6639(1.7906-3.5371) 0.8571(0.3769-1.3374)

[0511] 1 LCN24.28e-04 Up 943.0336(525.1126-1360.9546) 161.3036(67.3015-255.3057) LINC015554.31e-04 Up 1.1513(0.8293-1.4733) 0.4107(0.1565-0.6649)

[0512] CBX24.76e-04 Up 3.4034(2.2015-4.6053) 1.1071(0.687-1.5273)

[0513] GRM86.10e-04 Up 6.1849(5.0473-7.3225) 3.1786(1.9038-4.4533)

[0514] MMP77.65e-04 Up 39.7227(26.7145-52.7309) 12.4821(3.505-21.4593)

[0515] NOS2 7.92e-04 Up 41.916(32.0405-51.7914) 17.5(7.2993-27.7007)

[0516] 7 LY6G6F-LY6G6D 8.70e-04 Up 26.3445(15.2665-37.4226) 6.3571(2.7688-9.9455) AL121761.1 8.83e-04 Up 3.8319(2.0603-5.6035) 0.7143(0.323-1.1056)

[0517] ZIC20.001 Up 17.084(10.0708-24.0973) 3.8929(0.2356-7.5501)

[0518] 0 CNTD2 0.001 Up 4.0336(2.6431-5.4242) 1.2321(0.2822-2.182)

[0519] 1 SOX1 0.001 Up 2.3782(1.206-3.5503) 0.3571(0.0754-0.6388)

[0520] FIBCD1 0.001 Up 14.3782(9.3139-19.4424) 5.0893(2.7584-7.4202)

[0521] OTX1 0.001 Up 1.916(1.275-2.5569) 0.6071(0.1428-1.0715)

[0522] TNFSF90.001 Up 6.5798(3.7005-9.4592) 1.6429(0.9475-2.3383)

[0523] MMP12 0.001 Up 93.9664(55.0754-132.8574) 27.7143(18.8073-36.6213) AC005833.1 0.001 Up 12.2857(9.4992-15.0723) 6.0714(3.4766-8.6663) 7RAET1L 0.002 Up 2.6555(1.5695-3.7414) 0.6964(0.1758-1.217)

[0524] PLA2G3 0.002 Up 1.8403(1.2397-2.441) 0.6071(0.1235-1.0907)

[0525] MUC170.002 Up 64.9328(42.6071-87.2584) 26.6607(17.702-35.6195) 0APCDD1 0.002 Up 135.605(99.0953-172.1148) 65.4643(40.1012-90.8273)

[0526] 1 PRKCG 0.002 Up 1.7479(1.1448-2.351) 0.7143(0.4656-0.963)

[0527] HTR1D 0.002 Up 8.8403(5.4859-12.1948) 2.7857(0.8992-4.6723)

[0528] NOTUM 0.002 Up 21.2857(12.0172-30.5543) 5.4643(1.1816-9.747)

[0529] NPW 0.003 Up 5.7815(4.0065-7.5566) 2.4643(1.2451-3.6835)

[0530] GJB40.003 Up 2.1429(1.6612-2.6245) 0.8214(0.1136-1.5292)

[0531]

[0532] _

[0533] Table 47: List C2 of t-test Results for comparison between HG. AP vs healthy

[0534]

[0535] TPX2 1.20e-05 Up 99.2083(73.8258-124.5909) 30.7679(22.8464-38.6893) NFE2L3 1.23e-05 Up 104.9583(76.3739-133.5427) 28.1786(20.6685-35.6887) TGIF1 1.25e-05 Up 205.4583(155.8424-255.0742) 71.9107(55.9043-87.9171) PPA1 1.36e-05 Up 402.6667(301.7957-503.5377) 132.5(98.6118-166.3882) VWA2 1.44e-05 Up 80.3333(58.8638-101.8028) 22.8393(14.828-30.8505) MYC 1.47e-05 Up 301.3333(215.1123-387.5544) 72.9643(52.7753-93.1533) IQANK1 1.50e-05 Up 41.1667(29.777-52.5563) 11.0179(8.0667-13.969)

[0536] HES6 1.53e-05 Up 172.9583(129.2111-216.7056) 56.7857(42.2802-71.2913) SAPCD2 1.58e-05 Up 79.2083(59.1481-99.2686) 26.125(19.8459-32.4041) FOXP4-AS1 1.78e-05 Up 11.8333(8.689-14.9777) 3.5536(2.4418-4.6653) PFDN4 1.91e-05 Up 133.7917(101.1728-166.4105) 48.7857(39.369-58.2024) ECT2 2.08e-05 Up 117(85.3679~148.6321) 35.0357(25.7016~44.3698)

[0537] RAB15 2.22e-05 Up 72.1667(54.0123-90.3211) 25.4464(20.7244-30.1685) BACE22.23e-05 Up 422.75(307.2902-538.2098) 125.5357(94.6866-156.3848) OGFRP1 2.39e-05 Up 6.125(4.5732-7.6768) 2.1071(1.5079-2.7064)

[0538] MDFI 2.58e-05 Up 3.5833(2.4842-4.6825) 0.7857(0.4981-1.0733)

[0539] AXIN22.63e-05 Up 349.4167(241.5513-457.2821) 75.75(51.6046-99.8954)

[0540] SP5 2.64e-05 Up 24.7917(16.7672-32.8161) 4.4464(2.7574-6.1355)

[0541] LIPG 2.68e-05 Up 82.5833(59.4574-105.7093) 23.8929(17.9596-29.8261) CDCA72.84e-05 Up 245.1667(186.4397-303.8936) 94.2321(69.5077-118.9566) LINC02163 3.33e-05 Up 3.1667(1.9942-4.3392) 0.25(0.0441-0.4559)

[0542] LGR5 3.39e-05 Up 176.6667(117.4491-235.8842) 29.0536(14.035-44.0721) CSE1L 3.62e-05 Up 144.3333(107.2572-181.4095) 52.1964(41.804-62.5889) AC008966.3 3.71e-05 Up 5.5833(4.1263-7.0403) 1.9107(1.3016-2.5199) GRIN2D 3.77e-05 Up 22.8333(14.9015-30.7651) 3.2857(1.8416-4.7299) BLACAT1 3.96e-05 Up 9.4167(5.9706-12.8627) 0.9643(0.4411-1.4875)

[0543] C2 4.14e-05 Up 44.5(30.6627~58.3373) 10.4107(6.2828~14.5386)

[0544] CKAP24.15e-05 Up 97.25(71.1099-123.3901) 32.6964(24.1583-41.2345)

[0545] CKS24.41e-05 Up 205.3333(145.1624-265.5042) 57.7321(39.4376-76.0266) PPM1H 4.48e-05 Up 33.7917(23.8216-43.7617) 9.4464(6.8221-12.0708)

[0546] TGFBI 4.50e-05 Up 580.875(406.6229-755.1271) 155.4643(109.1406-201.788) HOXA94.78e-05 Up 199.625(150.0846-249.1654) 77.5(57.9288-97.0712)

[0547] ETS25.00e-05 Up 921.5(693.1834-1149.8166) 361.5(274.0043-448.9957) LINC011245.04e-05 Up 2.625(1.8903-3.3597) 0.8214(0.5321-1.1108) LINC01315 5.33e-05 Up 17.875(13.0183-22.7317) 6.0714(4.3671-7.7758) SLC7A5 5.51e-05 Up 27.625(19.5959-35.6541) 8.3036(6.0479-10.5592) MAD2L1 5.64e-05 Up 110.875(79.6277-142.1223) 35.7143(26.4663-44.9623) CYP39A1 6.37e-05 Up 18.0417(13.0245-23.0588) 6.0536(4.4279-7.6793) HMGA1 6.53e-05 Up 479.1667(351.3735-606.9599) 175(135.8741-214.1259) RAD54B 6.81e-05 Up 15.6667(11.5752-19.7581) 5.9821(4.8249-7.1394) PROX1 7.09e-05 Up 106.4583(74.2829-138.6338) 30.4286(20.8436-40.0135) JPH1 7.16e-05 Up 45.5833(31.9966-59.1701) 13.5893(9.9435-17.2351)

[0548] CLDN1 7.28e-05 Up 106.4167(77.0958-135.7375) 28.25(5.4956-51.0044) TNFSF157.30e-05 Up 33.75(24.9556-42.5444) 12.9107(9.8963-15.9251) ZC3HAV1L 7.66e-05 Up 1.7917(1.2079-2.3754) 0.4107(0.2015-0.6199)

[0549] EFNA3 7.80e-05 Up 36.625(24.6856-48.5644) 8.7857(6.0486-11.5228)

[0550] RNF43 7.90e-05 Up 154.7083(109.8102-199.6065) 48.9821(33.6021-64.3622) ZNF7928.00e-05 Up 11.7083(8.0706-15.3461) 3.2321(2.3301-4.1342) AC106900.1 8.10e-05 Up 2.5(1.693-3.307) 0.6071(0.3434-0.8709)

[0551] AC090116.1 8.43e-05 Up 6.2917(3.9672-8.6161) 0.8929(0.285-1.5007)

[0552] UBE2C 8.92e-05 Up 144.6667(99.1987-190.1346) 39.6607(28.4022-50.9192) MARCKSL1 9.56e-05 Up 977.9167(706.7474-1249.0859) 348.3929(253.661-443.1247) C2CD4A 9.83e-05 Up 58.2083(35.4463-80.9704) 6.375(3.1864-9.5636)

[0553] MELK 1.05e-04 Up 55.375(38.7436-72.0064) 17.1964(11.8794-22.5135)

[0554] NXT1 1.06e-04 Up 41.4167(30.1205-52.7129) 15.4107(11.4521-19.3693) CEMIP 1.08e-04 Up 120.4167(78.4421-162.3912) 24.8929(13.8857-35.9) EEF1AKMT4 1.10e-04 Up 17.3333(12.4713-22.1954) 6.2143(4.6422-7.7864) EPOP 1.15e-04 Up 14.7917(9.3626-20.2207) 2.5714(1.604-3.5388)

[0555] STMN1 1.17e-04 Up 347.3333(247.5033-447.1634) 120.9464(91.761-150.1319) KIF18A 1.22e-04 Up 26.0417(18.299-33.7844) 8.5714(6.4267-10.7162) TOP2A 1.24e-04 Up 360.0417(256.4792-463.6041) 124.9107(89.8503-159.9711) SKA3 1.28e-04 Up 29(20.8395-37.1605) 10.5179(7.7278-13.3079) PLEKHS1 1.28e-04 Up 94(66.1354-121.8646) 31.0536(22.0347-40.0724) NCOA7 1.32e-04 Up 215.5417(154.5381-276.5452) 79.3393(65.0914-93.5871) DACH1 1.35e-04 Up 144.0417(100.8229-187.2605) 47.7679(37.8246-57.7111) KIF4A 1.37e-04 Up 34.8333(24.7353-44.9314) 12.0357(8.4135-15.6579) ACBD7 1.40e-04 Up 6.2083(4.3241-8.0926) 1.9821(1.3683-2.596) AL591069.1 1.45e-04 Up 6.2917(4.533-8.0503) 2.3214(1.6399-3.003) PRRT3-AS1 1.52e-04 Up 7.375(5.3259-9.4241) 2.6964(1.7494-3.6435) NEK2 1.53e-04 Up 49.375(33.3499-65.4001) 13.8571(9.2777-18.4366) FGFRL1 1.56e-04 Up 91.4583(63.6157-119.301) 29.8393(21.7424-37.9362) MZT1 1.58e-04 Up 101.5833(71.8837-131.283) 35.9464(27.4982-44.3946) SNORA26 1.58e-04 Up 2.9167(2.1009-3.7324) 1.0893(0.7775-1.4011) NPM1 1.59e-04 Up 654.7917(472.3628-837.2206) 250.5714(193.5916-307.5512) GPX2 1.76e-04 Up 739.1667(528.122-950.2113) 275.2143(208.1434-342.2852) BUB1 1.78e-04 Up 48.9167(33.7612-64.0721) 15.6071(10.713-20.5013) ITGA6 1.78e-04 Up 1163.25(833.8964-1492.6036) 439.5714(332.9796-546.1633) PRKDC 1.79e-04 Up 361.4167(261.1429-461.6904) 140.7857(107.3224-174.2491) MEST 1.81e-04 Up 64.9583(45.33-84.5867) 21.6071(14.4027-28.8116) MTHFD1L 1.93e-04 Up 65.5(45.3226-85.6774) 21.5179(15.1929-27.8428) SMKR1 1.93e-04 Up 3.7083(2.2697-5.1469) 0.5893(0.2011-0.9775) MND1 1.94e-04 Up 28.3333(19.7482-36.9185) 9.5893(6.752-12.4265) PLEKHB1 2.16e-04 Up 18.4583(12.7102-24.2064) 6.0893(4.428-7.7506) LINC009202.19e-04 Up 14.625(9.5827-19.6673) 3.8036(2.4074-5.1997) SLC35E42.19e-04 Up 22.25(15.55-28.95) 7.7857(5.6175-9.954)

[0556] BUB1B 2.21e-04 Up 37.375(26.4664-48.2836) 13.5536(9.221-17.8862) ZNF2392.24e-04 Up 14.9167(10.1476-19.6858) 4.75(3.6604-5.8396) LINC008582.28e-04 Up 5.0833(3.0452-7.1215) 0.75(0.307-1.193)

[0557] ZNRF3 2.29e-04 Up 104(75.3502-132.6498) 42.3393(32.9472-51.7314) ANLN 2.29e-04 Up 78.0833(50.9609-105.2058) 20.5179(15.1093-25.9265) NANOS3 2.29e-04 Up 2.2917(1.407-3.1764) 0.4107(0.2144-0.607) AC007342.5 2.30e-04 Up 17.7917(12.3398-23.2435) 6.1429(4.6388-7.6469) C19orf482.46e-04 Up 84.9167(58.9642-110.8691) 30(23.7695-36.2305) CDH3 2.70e-04 Up 68.0417(42.1788-93.9045) 13.6964(7.143-20.2498) HIST3H2A 2.71e-04 Up 32.5(21.2202-43.7798) 8.9286(6.731-11.1262) ACTL102.71e-04 Up 7.2917(5.0976-9.4857) 2.5893(1.7321-3.4465) CKAP2L 2.91e-04 Up 35.0833(24.3156-45.8511) 12.4107(8.9284-15.893) PLCB42.94e-04 Up 346.5833(255.9314-437.2352) 152.3571(113.803-190.9113) CD3EAP 2.96e-04 Up 19.375(13.348-25.402) 6.8214(5.3073-8.3356) AC007342.9 3.04e-04 Up 11.7083(7.8978-15.5188) 3.75(2.6332-4.8668) TTK 3.12e-04 Up 44.8333(31.3114-58.3553) 16.4464(11.7842-21.1087) AC124067.4 3.15e-04 Up 15.4583(10.6037-20.3129) 5.2321(3.4368-7.0275) PAFAH1B3 3.18e-04 Up 41.5417(27.9949-55.0884) 13.5(10.0735-16.9265) TDGF1 3.20e-04 Up 31.8333(19.9226-43.744) 7.2143(4.2951-10.1335) SLC28A3 3.21e-04 Up 32.5833(19.5565-45.6102) 5.8393(3.6806-7.9979) EXO1 3.23e-04 Up 20.0417(13.346-26.7373) 6.125(4.117-8.133)

[0558] SLC04A1-AS1 3.34e-04 Up 8.8333(5.3476-12.3191) 1.6964(1.0629-2.33) KIF24 3.40e-04 Up 5.875(4.0692-7.6808) 2.1071(1.4679-2.7464)

[0559] ETV43.46e-04 Up 56.8333(32.2925-81.3741) 6.9286(3.9689-9.8882) RACGAP1 3.46e-04 Up 69.1667(47.271-91.0623) 23.8036(16.7886-30.8185) ERCC6L 3.52e-04 Up 11.9167(7.787-16.0463) 3.4821(2.6065-4.3578) RCN1 3.59e-04 Up 132.625(91.2616-173.9884) 46.7679(32.1842-61.3515) AL590483.4 3.64e-04 Up 6.1667(3.9755-8.3579) 1.6607(1.0002-2.3212) CDK1 3.71e-04 Up 115.1667(76.3527-153.9807) 35.8393(25.4883-46.1903) CDCA4 3.83e-04 Up 34.8333(23.5428-46.1239) 11.9107(9.2698-14.5516) AC010542.5 4.02e-04 Up 4.1667(2.7542-5.5791) 1.2679(0.7767-1.759) SLC05A1 4.06e-04 Up 11.7917(8.1507-15.4326) 4.375(3.2613-5.4887) DLGAP1-AS24.10e-04 Up 18.7083(12.6089-24.8078) 6.2321(4.1691-8.2952) ASCL24.30e-04 Up 230.75(144.3494-317.1506) 55.9107(30.2152-81.6063) SH3TC24.34e-04 Up 9.625(6.2176-13.0324) 2.7321(1.7063-3.7579) GPR194.36e-04 Up 2.5417(1.6353-3.448) 0.7143(0.4604-0.9682) SLCO4A1 4.41e-04 Up 64.0833(40.6481-87.5186) 17.4643(13.9962-20.9324) RNF183 4.50e-04 Up 34.8333(20.4367-49.23) 6.2857(4.525-8.0464) SLC12A9-AS1 4.57e-04 Up 1.875(1.3138-2.4362) 0.6607(0.3248-0.9967) DBNDD1 4.59e-04 Up 3.4167(2.1908-4.6425) 0.9643(0.6496-1.2789) TRIP13 4.75e-04 Up 42.5417(26.6862-58.3971) 11.0893(7.8441-14.3345) AJUBA 4.75e-04 Up 23.2917(14.6303-31.9531) 6.0357(3.8812-8.1902) ARHGEF38-IT1 4.91e-04 Up 2.9583(1.9507-3.9659) 0.9286(0.579-1.2781) FBXO5 4.98e-04 Up 41.2917(27.526-55.0573) 14.0179(10.718-17.3178) SKA1 5.04e-04 Up 24.7083(15.9119-33.5047) 7.25(4.9315-9.5685)

[0560] CXCL3 5.29e-04 Up 342.5(201.0989-483.9011) 63.0357(25.1988-100.8727) ALKAL1 5.40e-04 Up 5.4583(3.4896~7.4271) 1.5357(0.8739~2.1976) RANBP1 5.40e-04 Up 295(201.7785-388.2215) 107.8571(72.7043-143.01) GINS1 5.51e-04 Up 55.0417(36.1655-73.9178) 18(13.4492-22.5508) NUP62CL 5.56e-04 Up 9.875(6.4893-13.2607) 3.1429(1.9914-4.2944) C2CD4B 5.59e-04 Up 32.2083(20.5228-43.8938) 9.3036(6.4507-12.1565) CDC205.63e-04 Up 83.25(57.2101-109.2899) 31.1071(21.1242-41.09) IQGAP3 5.68e-04 Up 43.9167(28.6065-59.2268) 13.875(9.8027-17.9473) KIF2C 5.81e-04 Up 39.625(26.8998-52.3502) 14.5536(10.6052-18.502) NUF25.89e-04 Up 49.7083(33.3606-66.0561) 17.5(12.3026-22.6974) LINC025626.01e-04 Up 27(19.472-34.528) 11.8929(8.7116-15.0741) HSPE1 6.12e-04 Up 758.0417(532.9982-983.0851) 309.6964(220.2548-399.1381) CCNB1 6.12e-04 Up 119.875(79.3827-160.3673) 40.5179(28.0242-53.0115) DLGAP5 6.19e-04 Up 48.2083(32.7204-63.6962) 17.625(12.0655-23.1845) CENPA 6.25e-04 Up 33.7917(22.5532-45.0301) 11.9107(8.7942-15.0272) AC092718.46.37e-04 Up 21.5833(14.0926-29.074) 7.1429(5.5835-8.7022) RAN 6.47e-04 Up 721.9583(494.6361-949.2806) 277.875(204.6887-351.0613) IFITM3 6.51e-04 Up 566.7083(377.2922-756.1244) 197.1786(136.9484-257.4087) HS6ST27.05e-04 Up 16.4167(9.0197-23.8137) 2.3571(1.1493-3.565) CASC97.13e-04 Up 29.2083(20.4053-38.0113) 11.5179(7.1915-15.8442) LINC013577.27e-04 Up 3.375(2.0064-4.7436) 0.75(0.3704-1.1296)

[0561] SALL47.32e-04 Up 11.9167(7.5162-16.3172) 3.5(2.3479-4.6521)

[0562] CENPI 7.33e-04 Up 12.5417(8.2211-16.8623) 4.25(3.0072-5.4928) FAM72D 7.41e-04 Up 3.1667(1.9876-4.3458) 0.8393(0.3241-1.3545) KDELC1P1 7.51e-04 Up 2.4167(1.5282-3.3052) 0.6964(0.382-1.0109) LRRIQ47.51e-04 Up 6.5417(3.9209-9.1624) 1.5536(0.9159-2.1912) CCNA27.54e-04 Up 78.9167(53.2592-104.5741) 29.3571(20.5336-38.1807) C2CD4D 7.57e-04 Up 4.4583(2.9487-5.9679) 1.5357(0.9953-2.0761) LINC02577 8.07e-04 Up 1.9167(0.9773-2.8561) 0.1607(0.0491-0.2723) LMNB28.26e-04 Up 178.7917(120.5473-237.036) 67.7143(48.8669-86.5617) AL049873.1 8.38e-04 Up 63(43.4427-82.5573) 25.2321(17.5158-32.9484) KIF18B 8.48e-04 Up 37.6667(24.7493-50.584) 13.2321(9.4997-16.9646) DDIAS 8.48e-04 Up 17.75(11.896-23.604) 6.5714(4.5513-8.5916)

[0563] SLC6A6 8.80e-04 Up 15.25(9.5042-20.9958) 4.5179(3.2432-5.7925)

[0564] TP53 8.83e-04 Up 224.5(152.613-296.387) 88.6786(66.5203-110.8369) CDKN3 8.96e-04 Up 79.9583(52.9819-106.9348) 28.9464(20.2659-37.627) CELSR3 9.42e-04 Up 13.8333(8.875-18.7917) 4.5893(3.2855-5.893) LINC01301 9.54e-04 Up 6.4167(3.9328-8.9005) 1.8036(1.1963-2.4109) EGFL69.64e-04 Up 4.5833(2.5376-6.6291) 0.7857(0.2758-1.2957)

[0565] CEP55 9.67e-04 Up 56.7917(36.0228-77.5605) 17.9643(11.7263-24.2023) RASSF10 9.80e-04 Up 14.0833(9.2432-18.9234) 4.9286(3.1333-6.7238) SNHG60.001 Up 144.4583(93.3373-195.5794) 48.5357(30.9536-66.1179) TNFRSF10B 0.001 Up 57.9583(38.073-77.8437) 21.0536(15.4453-26.6618) TSACC 0.001 Up 1.2083(0.7428-1.6739) 0.3393(0.1756-0.503)

[0566] E2F70.001 Up 14.5(8.7749-20.2251) 4.0714(3.0263-5.1166)

[0567] LRP40.001 Up 91.5(59.1894-123.8106) 31.4464(20.6421-42.2507)

[0568] CDC60.001 Up 48.3333(29.8141-66.8526) 14.6786(10.6529-18.7042) PSAT1 0.001 Up 57.9583(33.1946-82.722) 13.1429(8.5694-17.7163) KPNA20.001 Up 184.625(111.1257-258.1243) 50.9821(33.9668-67.9975) CYP19A1 0.001 Up 1.5833(0.9744-2.1923) 0.4643(0.2667-0.6618) RRM20.001 Up 237.125(145.5985-328.6515) 71.5(51.039-91.961) AC026271.1 0.001 Up 5.0417(3.1513-6.9321) 1.5893(1.0304-2.1482)

[0569] EPHB30.001 Up 153.1667(96.0411-210.2923) 49.25(33.7142-64.7858) AC012494.20.001 Up 3.4583(1.6031-5.3135) 0.1429(-0.1095-0.3953) CADPS 0.001 Up 61.5417(38.5219-84.5614) 20.125(15.1872-25.0628) INHBA 0.001 Up 63.0417(37.5709-88.5125) 16.4286(7.9262-24.931)

[0570] STC20.001 Up 16.0833(8.9488-23.2178) 3.3036(1.8484-4.7587)

[0571] IPO40.001 Up 5.25(3.3979-7.1021) 1.8929(1.3484-2.4373)

[0572] GRIN2B 0.001 Up 34(18.9245-49.0755) 6.75(2.4642-11.0358)

[0573] E2F1 0.001 Up 25.4167(16.4065-34.4268) 9.0357(6.0738-11.9976)

[0574] RPS2P70.001 Up 649.0833(390.2718-907.8948) 189.5(150.5785-228.4215) LGR60.001 Up 23.0417(14.3214-31.7619) 7.4464(5.4647-9.4282)

[0575] SORD 0.001 Up 25.9167(15.1677-36.6657) 6.7143(4.1025-9.3261)

[0576] XKRX 0.001 Up 4.625(2.8517-6.3983) 1.3929(0.7516-2.0341)

[0577] C17orf770.001 Up 4.8333(2.9299-6.7367) 1.1964(0.1694-2.2234)

[0578] MEX3A 0.001 Up 26.75(16.3318-37.1682) 8.2857(6.3642-10.2072)

[0579] OPRD1 0.001 Up 4.5417(2.5378-6.5455) 1(0.677-1.323)

[0580] GATA2-AS1 0.001 Up 8.625(5.159-12.091) 2.375(1.2532-3.4968)

[0581] UBE2T 0.001 Up 85.5417(54.2835-116.7998) 29.75(20.8589-38.6411) AL135926.20.001 Up 5.375(3.083-7.667) 1.3214(0.8004-1.8425) LINC017030.001 Up 2(1.2847-2.7153) 0.6964(0.4125-0.9804)

[0582] TMEM211 0.001 Up 5(2.8041-7.1959) 1.1071(0.5603-1.654)

[0583] LINC003460.001 Up 2.7917(1.7802-3.8031) 0.9643(0.5962-1.3324) HIST1H2BL 0.002 Up 4.4167(2.3112-6.5222) 0.7321(0.3993-1.065) MMP100.002 Up 16.4583(8.9252-23.9914) 3.2321(1.7442-4.7201)

[0584] TUBBP50.002 Up 10.0833(6.2375-13.9292) 3.2321(2.0087-4.4556) AL354953.1 0.002 Up 6.3333(3.5977-9.069) 1.5357(0.9424-2.129)

[0585] CBX20.002 Up 10(4.872-15.128) 1.1071(0.687-1.5273)

[0586] AC007688.1 0.002 Up 2.5417(1.5693-3.514) 0.8214(0.5321-1.1108)

[0587] GAS50.002 Up 260.25(169.8631-350.6369) 99.3214(68.5237-130.1191) MSLN 0.002 Up 34.2083(16.2466-52.1701) 3.2143(2.0568-4.3718) LNCTAM34A 0.002 Up 6.5417(4.3143-8.769) 2.5536(1.7239-3.3832) VPS9D1-AS1 0.002 Up 5.6667(3.1372-8.1962) 1.25(0.6303-1.8697) CEACAM60.002 Up 1284.125(790.6455-1777.6045) 421.3036(295.5897-547.0174) CCNO 0.002 Up 26.5417(16.2089-36.8744) 8.625(6.3673-10.8827) RPL10P130.002 Up 1.8333(1.059-2.6076) 0.4643(0.1942-0.7343)

[0588] PHLDA1 0.002 Up 197.9583(115.3711-280.5455) 54.4464(32.7296-76.1632) CCL260.002 Up 3.0833(1.4554-4.7112) 0.3036(0.1273-0.4799)

[0589] LINC009700.002 Up 2.875(1.47-4.28) 0.4643(0.1942-0.7343)

[0590] AC239800.20.002 Up 5.5(3.1506-7.8494) 1.4286(0.763-2.0941)

[0591] RAD51AP20.002 Up 3.25(1.9485-4.5515) 1(0.6462-1.3538)

[0592] HOXB60.002 Up 149.5(97.7795-201.2205) 59.0357(41.458-76.6134) C11orf53 0.002 Up 9.1667(5.9444~12.3889) 3.5536(2.5009~4.6063)

[0593] TFAP2A-AS1 0.002 Up 2.8333(1.3777-4.289) 0.3571(0.132-0.5822)

[0594] GGH 0.002 Up 285.5833(188.2061-382.9606) 117.1607(88.7982-145.5232) TICRR 0.002 Up 10.625(6.672-14.578) 3.6964(2.2602-5.1326)

[0595] AC009005.1 0.002 Up 2.8333(1.5717-4.095) 0.6786(0.4031-0.9541) C6orf2230.002 Up 12.0833(6.582-17.5846) 2.6786(1.3735-3.9837)

[0596] NOX1 0.002 Up 278.8333(182.4403-375.2264) 112.1964(82.409-141.9839) TMEM132A 0.002 Up 8.2083(4.7644-11.6523) 2.2679(1.2345-3.3013) C3orf670.002 Up 7.625(4.8412-10.4088) 2.7321(1.6339-3.8304) TNFRSF11B 0.002 Up 33.625(20.0955-47.1545) 10.5179(7.2265-13.8093) KIAA12570.002 Up 8.5417(5.0619-12.0215) 2.625(1.8822-3.3678) AC099792.1 0.002 Up 3.4583(1.7375-5.1791) 0.5536(0.2837-0.8234) UHRF1 0.002 Up 58.375(33.7081-83.0419) 16.5714(11.4374-21.7054) TEX450.002 Up 5.4583(3.3197-7.5969) 1.7857(1.0973-2.4741)

[0597] RUBCNL 0.002 Up 107.5417(70.3244-144.759) 43.1786(29.4985-56.8587) PIMREG 0.002 Up 16.5(10.2294-22.7706) 5.8036(3.9248-7.6823)

[0598] OXGR1 0.002 Up 15.7083(8.4397-22.9769) 3.5536(2.4886-4.6186)

[0599] C2orf700.002 Up 5.8333(3.4039-8.2628) 1.6964(0.978-2.4149) 267 LINC011860.002 Up 3.5(1.8481-5.1519) 0.7321(0.4237-1.0406)

[0600] 268 EDAR 0.002 Up 11.9583(6.5243-17.3924) 2.8929(2-3.7857)

[0601] 269 SNRPEP20.002 Up 3.5(2.1705-4.8295) 1.2143(0.7306-1.698)

[0602] 270 AP005271.1 0.002 Up 1.375(0.7066-2.0434) 0.25(0.0713-0.4287)

[0603] 271 AC107075.1 0.002 Up 8.3333(5.0799-11.5867) 2.8214(1.8141-3.8288) 272 AC090371.20.002 Up 1.75(0.8586-2.6414) 0.2679(0.0947-0.441) 273 SNRPG 0.002 Up 243.4167(154.819-332.0143) 92.0536(59.8856-124.2215) 274 FIRRE 0.002 Up 9(4.7335-13.2665) 1.9643(1.4215-2.5071)

[0604] 275 CDCA20.002 Up 27.2083(16.4413-37.9754) 9.1964(6.3954-11.9974) 276 TUBB5 0.003 Up 715.25(445.7394~984.7606) 262.9286(185.7988~340.0583) 277 RPL22L1 0.003 Up 406.5417(212.42-600.6633) 87.3036(64.3338-110.2733) 278 ODC1 0.003 Up 317.5417(177.2042-457.8792) 86.4286(65.3985-107.4586) 279 RPL12P40.003 Up 32.125(19.5023-44.7477) 10.8929(6.6218-15.1639) 280 LINC008530.003 Up 2.1667(1.3252-3.0081) 0.75(0.46-1.04)

[0605] 281 TG 0.003 Up 2.5(1.4289-3.5711) 0.7143(0.3845-1.0441)

[0606] 282 CCL200.003 Up 261.125(134.0371-388.2129) 52.9643(28.3929-77.5356) 283 RPS7P100.003 Up 105.3333(64.3566-146.3101) 36.875(23.4319-50.3181) 284 CXCL20.003 Up 121.75(62.4118-181.0882) 23.9821(8.9753-38.989) 285 GMDS 0.003 Up 497.5(317.22-677.78) 199.5893(149.6981-249.4804) 286 LINC015490.003 Up 1.3333(0.6002-2.0665) 0.1429(0.0354-0.2503) 287 AC036176.3 0.003 Up 4.6667(2.9249-6.4084) 1.6429(0.7801-2.5056) 288 SNORA74D 0.003 Up 3.75(2.2441-5.2559) 1.2679(0.8271-1.7086) 289 CHRNA50.003 Up 9.5833(5.9277-13.239) 3.5714(2.5016-4.6412)

[0607] 290 LINC018070.003 Up 3.375(1.3834-5.3666) 0.1786(-0.0063~0.3635) 291 BMP70.003 Up 28.75(16.4426-41.0574) 8.8929(6.7906-10.9951)

[0608] 292 RPS4XP11 0.003 Up 69.125(42.6343-95.6157) 25.25(16.0595-34.4405) 293 CPNE70.003 Up 14.4583(7.2084-21.7082) 2.8036(1.66-3.9471)

[0609] 294 AC007342.40.003 Up 2.0833(1.1522-3.0145) 0.5714(0.3439-0.799) 295 KLHL320.003 Up 8.4583(5.0054-11.9113) 2.8929(2.2336-3.5522) 296 AC093866.1 0.003 Up 22.1667(9.5186-34.8148) 1.9821(0.6958-3.2685) 297 MIR16-20.003 Up 5.25(3.1507-7.3493) 1.7679(0.9685-2.5672)

[0610] 298 PBK 0.003 Up 60.125(34.9897-85.2603) 19.5536(13.4325-25.6747) 299 TNS40.003 Up 80.2917(37.8101-122.7732) 12.9286(8.5717-17.2855) 300 WDR720.003 Up 19.7083(10.1216-29.295) 4.4464(2.9576-5.9352) 301 LINC023130.003 Up 5.4167(3.2281-7.6052) 1.8929(1.3226-2.4631) 302 CRUDE 0.003 Up 51(28.4625-73.5375) 14.2321(6.7196-21.7447)

[0611] 303 AC016712.1 0.003 Up 5.2917(3.1915-7.3919) 1.8929(1.2681-2.5176) 304 CXCL160.003 Up 47.2917(25.1254-69.4579) 12.125(8.5349-15.7151) 305 CCDC1960.003 Up 6.4583(4.109-8.8077) 2.5536(1.5634-3.5437)

[0612] 306 SERPINB50.004 Up 124.9583(68.3623-181.5544) 31.5357(9.0216-54.0498) 307 GAPLINC 0.004 Up 4.2917(2.4054-6.1779) 1.25(0.6808-1.8192)

[0613] 308 FAM167A 0.004 Up 7.2083(4.5817-9.835) 2.875(1.8086-3.9414)

[0614] 309 YBX1 0.004 Up 600.4167(393.272-807.5613) 257.4464(169.6706-345.2222) 310 CYP4X1 0.004 Up 41.875(21.0702-62.6798) 9.25(6.1931-12.3069) 311 LINC017300.004 Up 4.8333(2.7923-6.8743) 1.625(1.2211-2.0289) 312 ATP6V1C20.004 Up 7.0833(3.8413-10.3254) 1.9107(0.932-2.8894) 313 MSX20.004 Up 40.1667(18.4034-61.9299) 6.1607(2.7048-9.6167)

[0615] 314 CYP4A22-AS1 0.004 Up 1.5(0.8411-2.1589) 0.4464(0.2364-0.6565) 315 AL606537.1 0.004 Up 4.6667(2.8984-6.4349) 1.75(0.9601-2.5399)

[0616] 316 SNORA330.004 Up 4.875(2.5279-7.2221) 1.1964(0.6746-1.7183)

[0617] 317 MMP3 0.004 Up 90.9583(43.0937-138.823) 16.2143(6.2617-26.1668) 318 ZNF6950.004 Up 2.25(1.1345-3.3655) 0.5179(0.3201-0.7156)

[0618] 319 AC016735.1 0.004 Up 1.7917(1.0345-2.5489) 0.5893(0.3351-0.8435) 320 PDZK1IP1 0.004 Up 175.2083(93.9165-256.5002) 49.5179(35.0716-63.9641) 321 ACAN 0.004 Up 4.9167(2.4359-7.3974) 1.0536(0.4314-1.6757)

[0619] 322 TDGF1P30.004 Up 5.625(2.8748-8.3752) 1.375(0.8028-1.9472)

[0620] 323 AL391056.1 0.004 Up 6.9583(3.7245-10.1922) 1.9643(1.3024-2.6261) 324 SNORD83A 0.005 Up 2.5417(1.1004-3.983) 0.3393(0.121-0.5576)

[0621] 325 LINC022530.005 Up 6.2083(2.5589-9.8578) 0.6071(-0.1306-1.3449) 326 PLAGL20.005 Up 82.25(48.0978-116.4022) 30.1071(24.3624-35.8519) LINC022540.005 Up 12.4167(5.086-19.7473) 1.2679(0.3077-2.228) BBOX1-AS1 0.005 Up 4.4167(2.0185-6.8148) 0.75(0.3012-1.1988)

[0622] ELFN1-AS1 0.005 Up 6.3333(3.1693-9.4973) 1.4643(0.7155-2.213) TRMT1120.005 Up 157.3333(94.5511-220.1156) 59.5714(39.9871-79.1558) GNL30.005 Up 86.3333(52.7298-119.9369) 33.9643(23.1205-44.8081) LINC024180.005 Up 16.375(6.5761-26.1739) 1.5536(0.3993-2.7079) CBX80.005 Up 19.375(10.7178-28.0322) 6.25(4.8401-7.6599)

[0623] CDC450.005 Up 22.6667(11.8876-33.4457) 6.1786(3.6205-8.7366) TNFSF90.005 Up 11.3333(4.9056-17.761) 1.6429(0.9475-2.3383)

[0624] GZMB 0.005 Up 9.75(5.3016-14.1984) 2.9821(1.9717-3.9926)

[0625] OR2I1P 0.005 Up 3.6667(1.7551-5.5782) 0.7679(0.3723-1.1634)

[0626] REG40.005 Up 1663.5(869.7988-2457.2012) 414.3393(94.5524-734.1262) TLX1 0.005 Up 3.9583(2.2534-5.6633) 1.3571(0.9136-1.8007)

[0627] KIF20A 0.005 Up 25.5833(14.281-36.8857) 8.375(5.5484-11.2016) SNRPGP20.005 Up 21.75(12.6199-30.8801) 7.4464(3.9062-10.9867) GAPDH 0.005 Up 3.6667(2.0591-5.2742) 1.2143(0.7415-1.6871)

[0628] FGGY 0.006 Up 61.625(30.4357-92.8143) 15.25(11.5858-18.9142) SHANK2-AS1 0.006 Up 2.2917(1.4158-3.1675) 0.8929(0.4635-1.3222) WNT20.006 Up 6.8333(2.9439-10.7228) 1.0536(0.3714-1.7357)

[0629] GHET1 0.006 Up 0.9583(0.5012-1.4155) 0.2679(0.1377-0.398) AC007608.20.006 Up 1.4583(0.5693-2.3474) 0.1429(0.0134-0.2723) AP005233.20.006 Up 12.9167(7.3218-18.5116) 4.4464(2.7535-6.1393) C1QBP 0.006 Up 132.5417(72.9758-192.1075) 42.0893(22.7299-61.4487) ASF1B 0.006 Up 41.5833(24.0112-59.1554) 15.0179(9.5575-20.4782) RPL39P3 0.006 Up 15.5833(9.3438-21.8228) 5.9464(3.4434-8.4495) CLDN20.006 Up 107.9167(47.8281-168.0052) 19.0893(8.8728-29.3058) LINC002390.006 Up 2.4583(1.3105-3.6062) 0.75(0.4884-1.0116) SERPINA1 0.006 Up 610.0417(300.1898-919.8935) 154.1786(107.5009-200.8563) PLEKHG40.006 Up 20.2083(12.064-28.3526) 7.75(4.6786-10.8214) TP53I11 0.006 Up 54.125(33.7826-74.4674) 22.7857(14.4677-31.1038) KLK120.006 Up 11.0417(4.6748-17.4085) 1.7143(0.8272-2.6013) LINC017480.006 Up 15.2917(7.0957-23.4877) 3.2679(1.9416-4.5941) AC027808.20.006 Up 1.625(0.9009-2.3491) 0.5(0.177-0.823)

[0630] NPFFR1 0.006 Up 5.5417(2.6482-8.4352) 1.3036(0.8645-1.7426)

[0631] KLK100.006 Up 18.3333(8.6475-28.0191) 4.0893(2.1845-5.9941)

[0632] TRIB30.006 Up 35.2083(17.5587-52.8579) 9.3214(6.1143-12.5286) AC022101.1 0.006 Up 13.4167(7.7488-19.0845) 5.0179(3.54-6.4957)

[0633] APIP 0.006 Up 127.7917(73.1824-182.401) 46.3571(29.8066-62.9077) AL161431.1 0.007 Up 6.3333(3.3432-9.3235) 1.5893(0.0105-3.1681) SNORD460.007 Up 4.6667(2.215-7.1183) 1.0536(0.442-1.6651)

[0634] NPSR1-AS1 0.007 Up 7.625(3.0945-12.1555) 0.9821(-0.0257~1.99)

[0635] OLFM40.007 Up 5522.6667(2328.0238-8717.3096) 902.4286(550.5311-1254.326) EIF1AXP1 0.007 Up 9.25(4.9758-13.5242) 2.9107(1.6226-4.1989) CCDC1920.007 Up 3.0833(1.7543-4.4123) 1.1071(0.6839-1.5304) LINC01811 0.007 Up 4.4583(1.9805-6.9362) 0.8571(0.3963-1.318) RPL34P180.007 Up 39.4583(25.2147-53.702) 17.4107(10.637-24.1844) L1TD1 0.007 Up 275(133.1381-416.8619) 66.4464(27.6952-105.1976) HSF1 0.007 Up 11.625(7.3917-15.8583) 4.9107(2.5664-7.255)

[0636] EVX1 0.007 Up 5.9167(2.4037-9.4296) 0.8571(0.3769-1.3374) AC090498.1 0.007 Up 13.0417(6.8941-19.1893) 4.0536(2.375-5.7322) HIST1H4I 0.007 Up 6.7917(3.7749-9.8085) 2.2679(1.0905-3.4452) HSPD1P1 0.007 Up 2.2083(1.0404-3.3763) 0.5179(0.2525-0.7832)

[0637] APEX1 0.008 Up 113.125(69.2304-157.0196) 48.3214(32.9462-63.6967) LY6G6F-LY6G6D 0.008 Up 76.375(27.0173-125.7327) 6.3571(2.7688-9.9455) PCSK1 0.008 Up 94.875(35.1118-154.6382) 10.5714(8.1578-12.9851) AL590708.1 0.008 Up 4.75(2.5996-6.9004) 1.6607(1.1468-2.1746)

[0638] KLF160.008 Up 14.625(8.5736-20.6764) 5.6964(3.4495-7.9434)

[0639] IER30.008 Up 12.75(6.5387-18.9613) 3.9286(2.9112-4.9459)

[0640] ASS1 0.008 Up 239(131.7133-346.2867) 85.2857(60.1362-110.4353) GMPR 0.008 Up 19.7083(10.1087-29.308) 5.9821(3.7118-8.2525) RPSA 0.008 Up 393.75(233.1-554.4) 156.4286(92.8064-220.0508) KRT18P130.008 Up 35.625(19.6721-51.5779) 12.4286(7.0852-17.7719) TEDC20.008 Up 5.2917(2.7022-7.8812) 1.5714(0.8459-2.297)

[0641] RPL18A 0.008 Up 726.8333(423.4265-1030.2402) 284.4107(177.3784-391.443) MSX1 0.008 Up 46.9583(19.7094-74.2073) 8.7143(5.4705-11.9581) AC020656.20.008 Up 15.8333(9.8985-21.7681) 6.8214(3.8793-9.7635) LINC025420.008 Up 3.5417(1.8119-5.2714) 1.0893(0.7236-1.455) EPHA20.008 Up 89.25(42.8862-135.6138) 24.1964(18.3695-30.0234) PDCD2L 0.009 Up 13.875(7.3853-20.3647) 4.5893(2.678-6.5006) AC009065.50.009 Up 5.625(3.0226-8.2274) 1.9107(1.1562-2.6652) EEF1B2P60.009 Up 72.5417(46.1029-98.9804) 32.6429(19.4712-45.8145) DMRTA20.009 Up 5.7083(2.0515-9.3652) 0.6071(0.0723-1.142) HSPA80.009 Up 433.6667(244.1923-623.1411) 158.1607(86.2441-230.0774) LRRC360.009 Up 5.625(2.9347-8.3153) 1.8393(1.1999-2.4787) RPL30P40.009 Up 23.2917(14.0777-32.5056) 9.7679(5.8489-13.6868) CHST40.009 Up 3.5417(1.1857-5.8976) 0.2857(0.0966-0.4748) SCARNA220.009 Up 25.6667(11.7899-39.5435) 6.375(4.2274-8.5226) S100P 0.009 Up 967.9583(547.8284-1388.0883) 360.3571(200.8299-519.8844) IGHGP 0.009 Up 233.9167(112.3173-355.516) 61.1607(24.0905-98.2309) PCSK90.009 Up 41.9167(22.3415-61.4918) 13.9107(7.1562-20.6652) AC104088.20.009 Up 2.2917(1.2538-3.3296) 0.8214(0.5062-1.1367) LINC016300.009 Up 2.5(0.8109-4.1891) 0.1786(0.0632-0.294)

[0642] PAX90.009 Up 5.5(2.8178-8.1822) 1.7143(0.942-2.4866)

[0643] AF064858.1 0.009 Up 7.75(4.4292-11.0708) 3.0536(2.0601-4.047) GDF150.010 Up 232.4167(86.1585-378.6749) 32.1786(22.3441-42.0131) AC007608.1 0.010 Up 9.9583(4.768-15.1487) 2.6964(1.3396-4.0533) MAP1S 0.010 Up 13.75(7.6546-19.8454) 5.1071(3.0634-7.1509) AC008481.1 0.010 Up 1.25(0.7181-1.7819) 0.4821(0.2655-0.6988) MMP70.010 Up 82.5417(31.5634-133.52) 12.4821(3.505-21.4593) AC144450.1 0.010 Up 1.5417(0.6882-2.3951) 0.3571(0.1439-0.5703) AL590438.1 0.010 Up 2.7917(1.5098-4.0735) 1(0.6282-1.3718) MRPL490.010 Up 21.7917(13.2742-30.3091) 9.3214(5.2661-13.3768) U2AF20.010 Up 45.0417(25.3168-64.7666) 17.5357(11.7358-23.3357) MELTF 0.010 Up 63.75(30.7499-96.7501) 18.7321(13.4063-24.058) FSIP2-AS20.011 Up 3.5833(2.2312-4.9355) 1.625(0.9881-2.2619) OTX1 0.011 Up 4.2917(1.5622-7.0211) 0.6071(0.1428-1.0715)

[0644] SLC35D3 0.011 Up 4.375(1.4368-7.3132) 0.4643(0.2876-0.6409) MIR3142HG 0.012 Up 37.3333(19.6606-55.0061) 13.0179(7.3057-18.73) PLK1 0.012 Up 34.5833(19.0864-50.0802) 13.1786(7.9-18.4571)

[0645] PKM 0.012 Up 411.3333(193.3667-629.3) 119.6786(84.1654-155.1918) XKR90.012 Up 10.0833(6.0737-14.093) 4.4821(2.9214-6.0428)

[0646] SMN1 0.012 Up 6.375(3.5035-9.2465) 2.5179(1.8404-3.1953) RPL26P190.012 Up 41.4167(22.6189-60.2144) 15.875(10.1986-21.5514) IFI60.012 Up 347.25(138.2734-556.2266) 71.7679(51.0182-92.5175) LINC026570.012 Up 1.5833(0.669-2.4976) 0.3571(0.132-0.5822) SH3BGRL30.012 Up 22.0833(10.8133-33.3534) 6.8036(3.3895-10.2176) PGAM1 0.012 Up 21.9583(11.7619-32.1548) 8.2857(5.7556-10.8159) HPDL 0.012 Up 24.2083(14.2197-34.197) 10.4643(6.7779-14.1507) AC120349.1 0.013 Up 3.3333(1.7898-4.8769) 1.2321(0.724-1.7402) FEZF1-AS1 0.013 Up 11.2917(3.8847-18.6987) 1.5357(0.6025-2.469) AC104088.3 0.013 Up 4.1667(2.0769-6.2565) 1.3571(0.7875-1.9268) SLC7A11 0.013 Up 79.4583(33.9039-125.0127) 20.1607(15.2726-25.0488) MYEOV 0.013 Up 27.625(11.5636-43.6864) 6.6429(4.1134-9.1724) 0ST40.014 Up 78.2917(42.5057-114.0776) 29.5(15.7602-43.2398) IGFL40.014 Up 1.7917(0.8435-2.7398) 0.5179(0.2073-0.8285)

[0647] ULBP30.014 Up 11.9167(5.0535-18.7798) 3(2.1244-3.8756)

[0648] GPRC5A 0.014 Up 587.125(293.7799-880.4701) 206.1071(158.5611-253.6531) LINC001140.014 Up 4.5833(2.3877-6.7789) 1.6964(1.1257-2.2672) SNORA80B 0.014 Up 2.375(0.7813-3.9687) 0.3214(0.1437-0.4991) LINC01411 0.014 Up 8.2917(2.2999-14.2834) 0.6071(0.2545-0.9598) PKD1L30.015 Up 1.1667(0.4442-1.8892) 0.2321(0.0971-0.3672) TRIM70.015 Up 23.9167(11.3693-36.464) 7.7143(5.453-9.9756) POU6F20.015 Up 6.3333(2.0948-10.5718) 0.9107(0.4419-1.3795) PURPL 0.015 Up 5.9583(2.3484-9.5683) 1.3393(0.7091-1.9695) RPL5P340.016 Up 72.0833(42.4642-101.7025) 32.3036(20.1244-44.4828) SPINK 40.016 Up 1025.25(544.638-1505.862) 389.4821(216.4551-562.5092) LAIR20.016 Up 4.9583(1.8994-8.0172) 1.0179(0.2596-1.7762)

[0649] CD550.016 Up 466.8333(193.526-740.1407) 121.5357(92.2342-150.8373) AL031710.20.016 Up 1.6667(0.763-2.5703) 0.5(0.2551-0.7449) PRSS220.016 Up 32.875(13.7047-52.0453) 8.5893(5.6112-11.5674) CXCL80.016 Up 109.75(39.837-179.663) 20.0357(2.9414-37.1301) SNRPEP40.016 Up 5.4583(2.3132-8.6035) 1.4107(0.5688-2.2526) CNTD20.016 Up 8.75(2.8079-14.6921) 1.2321(0.2822-2.182) AL441963.1 0.017 Up 2.125(0.9417-3.3083) 0.625(0.3879-0.8621) SLCO1B30.017 Up 28.875(8.0807-49.6693) 2.8571(1.1973-4.517) NPSRI 0.017 Up 4.8333(1.6865-7.9801) 0.7857(-0.1245-1.696) KDELR3 0.017 Up 70.6667(35.5435-105.7899) 25.6071(15.7563-35.458) PRDX1 0.017 Up 11.625(5.5327-17.7173) 3.6607(1.3876-5.9338) RNU5F-1 0.017 Up 5.6667(1.8721-9.4612) 0.9286(0.4081-1.449) DLX60.017 Up 4.5833(1.3773-7.7893) 0.5893(0.229-0.9496) CHI3L1 0.017 Up 19.75(10.6685-28.8315) 6.9643(1.5465-12.382) KRT80 0.017 Up 16.375(8.3827-24.3673) 4.4643(-1.3898-10.3184) CALR 0.017 Up 34.7083(18.8233-50.5933) 13.7679(7.1888-20.3469) PTPRD-AS1 0.018 Up 7.4583(4.0506-10.8661) 3.0714(1.9263-4.2166) REG1B 0.018 Up 389(84.2356-693.7644) 12.8036(-3.3621-28.9692) CACNG80.018 Up 5.1667(1.7985-8.5348) 0.9821(0.4805-1.4838) TBCAP1 0.018 Up 8.75(4.5712-12.9288) 3.375(1.9256-4.8244) NT5DC20.018 Up 6.625(2.5106-10.7394) 1.5(0.699-2.301)

[0650] RBM8B 0.019 Up 4.75(2.8606-6.6394) 2.2143(1.2579-3.1707)

[0651] PI30.019 Up 144.75(48.7887-240.7113) 26.875(14.6211-39.1289) AC007608.40.019 Up 57(25.8039-88.1961) 17.4107(7.2275-27.5939) UBE2S 0.019 Up 7(2.8032-11.1968) 1.8393(1.0771-2.6015)

[0652] EIF3FP30.020 Up 4.5833(2.4889-6.6778) 1.875(1.0083-2.7417) ACAT20.020 Up 3.4583(1.9082-5.0085) 1.4464(0.7749-2.118) AC002057.20.020 Up 1.6667(0.6809-2.6524) 0.4464(0.1915-0.7014) IL23A 0.021 Up 12.4167(4.2411-20.5923) 2.5(1.2872-3.7128) TUBB4B 0.021 Up 63.3333(32.3781-94.2886) 23.8929(11.6443-36.1414) CENPN 0.021 Up 7.3333(3.6507-11.0159) 2.8214(1.979-3.6638) LENG80.021 Up 15.9167(8.527-23.3063) 6.6607(4.1267-9.1948) ROBO20.021 Up 12.25(5.7915-18.7085) 4.4286(3.3478-5.5093) ESM1 0.021 Up 11.8333 (3.0996-20.5671) 1.3571(0.7144-1.9999) NKD1 0.021 Up 116.5833(50.7122-182.4545) 35.3929(16.5911-54.1946) CCDC330.021 Up 1.375(0.396-2.354) 0.1964(0.0482-0.3446) AC010547.20.022 Up 1.9583(0.4668-3.4499) 0.1786(0.0332-0.324) PLP20.022 Up 5.7083(2.5669-8.8498) 1.75(0.4741-3.0259)

[0653] NOS2 0.022 Up 61.7917(25.4724-98.111) 17.5(7.2993-27.7007) H3F3AP40.023 Up 14.7083(6.9516-22.465) 5.25(2.9569-7.5431) GAS6-AS1 0.023 Up 18.2083(8.7139-27.7028) 6.875(5.0063-8.7437) YTHDF2P1 0.023 Up 1.9583(0.8413-3.0754) 0.625(0.3879-0.8621) AL354743.20.024 Up 1.4167(0.383-2.4504) 0.1964(0.0239-0.369) SIGLEC120.024 Up 2.3333(1.1028-3.5639) 0.8571(0.5168-1.1975) ERFE 0.024 Up 4.5(1.3845-7.6155) 0.8393(0.3527-1.3258)

[0654] MCIDAS 0.025 Up 1.25(0.49-2.01) 0.3393(0.127-0.5516) AC093424.1 0.025 Up 1.7917(0.7426-2.8407) 0.5536(0.3091-0.7981) LIF 0.026 Up 15.625(5.6318-25.6182) 4.0357(2.4314-5.6401) AL606807.1 0.026 Up 1.375(0.4874-2.2626) 0.3393(0.1532-0.5254) PLA2G30.027 Up 2.6667(0.9204-4.4129) 0.6071(0.1235-1.0907) SETD6P1 0.027 Up 1.4167(0.6601-2.1732) 0.5179(0.2784-0.7573) ZIC20.027 Up 37.6667(8.2598-67.0735) 3.8929(0.2356-7.5501) AL589669.1 0.027 Up 7.8333(3.2894-12.3773) 2.5536(1.553-3.5542) FOXD1 0.027 Up 3.25(0.8998-5.6002) 0.5536(0.2561-0.851)

[0655] AC118754.1 0.028 Up 11.9167(3.5898-20.2435) 2.3571(0.9826-3.7316) PHLDA20.028 Up 124.625(49.0072-200.2428) 38.0357(27.1516-48.9199) NME2P1 0.028 Up 9.375(4.4195-14.3305) 3.4643(1.6982-5.2303)

[0656] CASC80.028 Up 4.8333(1.6767-7.99) 1.1607(0.3749-1.9465)

[0657] PPIAP220.028 Up 12.875(5.6515-20.0985) 4.4107(2.3365-6.485)

[0658] TRIM720.028 Up 14.9583(3.0641-26.8526) 1.4107(0.2199-2.6016)

[0659] RPL17P360.028 Up 18.25(8.3023-28.1977) 6.4821(3.1287-9.8355) TRMT112P60.028 Up 5.4167(2.0319-8.8015) 1.5179(0.7796-2.2561)

[0660] KLRK1 0.029 Up 3.625(1.7958-5.4542) 1.5(1.0102-1.9898)

[0661] COL11A1 0.029 Up 19.0833(4.7076-33.4591) 2.8036(1.6076-3.9995) LINC024890.029 Up 4.2917(1.4977-7.0857) 1.1071 (0.6513-1.563) AC004034.1 0.029 Up 1.7083(0.5706-2.846) 0.4107(0.1779-0.6435)

[0662] DUOX20.030 Up 489.7917(129.4164-850.1669) 84.0179(45.1508-122.8849) LINC018190.030 Up 24.75(4.3088-45.1912) 1.8571(0.8598-2.8545)

[0663] APLN 0.030 Up 9.9583(2.281-17.6357) 1.3571(0.7184-1.9959)

[0664] MORC40.030 Up 111.4583(36.8866-186.0301) 27.9464(21.1367-34.7562) ART30.031 Up 19(5.3069-32.6931) 3.7143(2.2956-5.1329)

[0665] SNORA80E 0.031 Up 3.625(1.2175-6.0325) 0.9107(0.4175-1.4039) AC004080.1 0.032 Up 2.9167(0.7459-5.0874) 0.5(0.1894-0.8106)

[0666] KLK60.033 Up 8.7083(3.7378-13.6789) 2.6071(-0.079~5.2933)

[0667] AMH 0.034 Up 4.4583(1.6135-7.3032) 1.2321(0.3565-2.1078)

[0668] PRKCG 0.034 Up 3.3333(0.9393-5.7274) 0.7143(0.4656-0.963)

[0669] AC007493.1 0.034 Up 2.7917(0.7956-4.7878) 0.5357(-0.0917~1.1632)

[0670] ASCL50.035 Up 1.4167(0.4057-2.4276) 0.3036(0.113-0.4941)

[0671] MT-ND1 0.035 Up 4708.375(2497.7141-6919.0359) 2154.4643(1270.0922-3038.8363) AC005833.1 0.035 Up 14.875(7.0995-22.6505) 6.0714(3.4766-8.6663)

[0672] FBXL160.035 Up 9.7917(3.2607-16.3226) 2.6429(1.5566-3.7291)

[0673] LINC015550.036 Up 1.75(0.5284-2.9716) 0.4107(0.1565-0.6649)

[0674] AL138885.3 0.036 Up 4.5833(2.0045-7.1622) 1.6071(0.5004-2.7139) AL133297.20.038 Up 2.5417(0.7941-4.2893) 0.6607(0.3844-0.937)

[0675] PF40.038 Up 7.625(2.9067-12.3433) 2.4821(1.3334-3.6309)

[0676] RPS250.039 Up 247.8333(119.866-375.8007) 104.7857(56.7093-152.8622) RAET1L 0.039 Up 5.7083(0.989-10.4277) 0.6964(0.1758-1.217)

[0677] AC002367.1 0.040 Up 0.875(0.1672-1.5828) 0.125(0.0356-0.2144)

[0678] SLC22A11 0.040 Up 5.2917(1.4649-9.1184) 1.1964(0.4079-1.985)

[0679] CXCL1 0.041 Up 430.5(90.8071-770.1929) 71.6429(22.9354-120.3504)

[0680] GAD1 0.041 Up 4(1.1935-6.8065) 1.0179(0.4714-1.5643)

[0681] KRT230.042 Up 18(3.7585-32.2415) 2.875(-0.2822~6.0322)

[0682] NPW 0.042 Up 9.875(2.8429-16.9071) 2.4643(1.2451-3.6835)

[0683] DHRS20.042 Up 5.4167(1.4342-9.3992) 1.2321(0.6151-1.8492)

[0684] DNAH20.043 Up 8.5(1.4551-15.5449) 1.1786(0.6858-1.6713)

[0685] AREG 0.043 Up 134.0417(43.7691-224.3142) 39.2321(22.9964-55.4679)

[0686] SOX1 0.043 Up 5.7083(0.545-10.8717) 0.3571(0.0754-0.6388)

[0687] AL359075.1 0.043 Up 1.7083(0.3247-3.092) 0.2679(0.1024-0.4333)

[0688] REG1A 0.044 Up 3059(587.3952-5530.6048) 484.5357(112.8535-856.218) SNORD3A 0.045 Up 192.4583(20.1566-364.7601) 15.25(3.7409-26.7591) C4BPA 0.046 Up 8.875(4.3436-13.4064) 3.6607(1.1494-6.172)

[0689] AC078993.1 0.046 Up 21.2917(4.3642-38.2191) 3.9107(1.625-6.1964)

[0690] FIBCD1 0.047 Up 28.7917(5.4701-52.1132) 5.0893(2.7584-7.4202)

[0691] TBX180.048 Up 6.7917(1.8125-11.7708) 1.7143(0.8633-2.5653)

[0692] AL121761.1 0.049 Up 8.4167(0.75-16.0833) 0.7143(0.323-1.1056) NDUFA4L20.049 Up 6.4583(0.9345-11.9822) 0.9107(0.5415-1.2799) LINC016590.050 Up 4.2083(1.9533-6.4634) 1.8929(1.3181-2.4676) AC004009.20.051 Up 4.125(0.4516-7.7984) 0.4643(0.2667-0.6618)

[0693] PLA2G4D 0.052 Up 7(3.4083-10.5917) 2.625(-0.0654~5.3154)

[0694] LINC024320.052 Up 10.7083(3.316-18.1007) 3.0893(0.7871-5.3915)

[0695] ZIC50.054 Up 10.0833(0.9349-19.2318) 1.0536(0.0215-2.0856)

[0696] AC010378.20.054 Up 1.5833(0.3079-2.8588) 0.3214(0.1229-0.5199) AC004540.20.055 Up 3.375(1.0695-5.6805) 1.0893(0.6492-1.5294) CACNA2D20.056 Up 30.3333(12.9027-47.764) 13.2143(10.6908-15.7377) IGHG30.058 Up 406.7917(99.1869-714.3965) 105.3036(47.918-162.6891) DUSP270.059 Up 48.9583(2.1698-95.7469) 3.8929(-0.4532~8.2389) SLC6A140.060 Up 77.5833(8.2142-146.9525) 10.9464(5.7194-16.1734) NMU 0.062 Up 13.75(4.9714-22.5286) 5.1786(2.8545-7.5026)

[0697] TNNT1 0.065 Up 7.875(0.5386-15.2114) 0.9286(-0.1497-2.0069) AL109615.3 0.065 Up 8.1667(0.0838-16.2495) 0.5893(0.2838-0.8947) NXF30.066 Up 8.3333(2.0656-14.601) 2.3214(0.7498-3.893)

[0698] CLCA1 0.066 Up 3476.25(1272.9697-5679.5303) 1392.3929(989.2431-1795.5426) ADGRF1 0.067 Up 10.9167(2.5889-19.2445) 3.125(2.136-4.114)

[0699] TRIM290.067 Up 30.25(11.1044~49.3956) 10.3214(0.018-20.6249) AC005256.1 0.068 Up 3.7083(0.1113-7.3053) 0.375(0.1324-0.6176) RPL10P150.068 Up 1.9167(0.7099-3.1234) 0.7679(0.449-1.0867)

[0700] KISS1R 0.068 Up 1.8333(0.2258-3.4409) 0.3393(0.1532-0.5254)

[0701] DLX6-AS1 0.069 Up 6.2083(0.6943-11.7224) 1.1071(0.5301-1.6842) PTP4A30.070 Up 36.125(10.7925-61.4575) 12.6429(9.1157-16.17)

[0702] MSH40.072 Up 2.375(0.4956-4.2544) 0.6429(0.3432-0.9425)

[0703] AFAP1-AS1 0.073 Up 5.5(0.0113-10.9887) 0.5179(0.2429-0.7928)

[0704] FEZF1 0.075 Up 5.5833(-0.2676~11.4343) 0.3036(0.0538-0.5533)

[0705] LEMD1 0.076 Up 4.75(-0.2093~9.7093) 0.2857(0.0121-0.5594)

[0706] USF1 0.076 Up 3.7917(0.4996-7.0837) 0.8036(0.2893-1.3179)

[0707] GRM80.076 Up 6.25(3.048-9.452) 3.1786(1.9038-4.4533)

[0708] H3F3AP60.077 Up 2.125(0.093-4.157) 0.3036(0.1793-0.4278)

[0709] NOTUM 0.077 Up 41.7083(1.3792-82.0374) 5.4643(1.1816-9.747) PNPLA30.077 Up 4.8333(2.0836-7.5831) 2.2321(1.2198-3.2445) TMEM178B 0.078 Up 13.0417(3.6767-22.4067) 4.5893(3.1209-6.0577) MMP120.078 Up 190.2917(8.1359-372.4474) 27.7143(18.8073-36.6213) BOK-AS1 0.086 Up 5.9583(-0.6441~12.5607) 0.2321(0.0481-0.4162)

[0710] LCN20.092 Up 1576.875(-87.9786~3241.7286) 161.3036(67.3015-255.3057) SAA20.093 Up 6.5417(0.7212-12.3621) 1.5536(0.6488-2.4584) HMGB1P60.095 Up 28.2917(3.6551-52.9282) 7.4464(4.9772-9.9157) RNY3 0.096 Up 2.25(0.377-4.123) 0.6607(0.3797-0.9417)

[0711] IGFL20.098 Up 5(1.1844-8.8156) 1.5893(0.0481-3.1305)

[0712] EEF1A1P90.099 Up 1.4583(0.0333-2.8834) 0.2679(0.1377-0.398)

[0713] CST1 0.105 Up 5.0417(0.2489-9.8344) 1.0179(-0.204~2.2397)

[0714] TCN1 0.106 Up 43(2.6285-83.3715) 9.3214(-0.4532~19.0961)

[0715] ULBP20.109 Up 6.5417(-1.0519-14.1352) 0.4107(0.1954-0.626)

[0716] IL1A 0.109 Up 5.75(-0.0868~11.5868) 1(0.2023-1.7977)

[0717] AL365226.20.109 Up 44.5(0.0985-88.9015) 8.5179(3.0274-14.0083) RETNLB 0.114 Up 291.7917(51.7356-531.8477) 99.2321(61.8005-136.6638) RPL13AP200.117 Up 135.6667(9.6639-261.6694) 35.7857(19.075-52.4964) REN 0.120 Up 4.375(-0.3809~9.1309) 0.6429(0.1414-1.1443)

[0718] AL022068.1 0.121 Up 5(0.8646-9.1354) 0.7143(0.8496~2.579)

[0719] LINC018330.125 Up 5.3333(0.4426-10.224) 1.5357(0.8719-2.1995) KCTD160.125 Up 12.25(-0.385~24.885) 2.4643(0.8543-4.0743)

[0720] SPP1 0.126 Up 87.0417(-3.6407-177.7241) 16.9107(5.3763-28.4452) LINC006590.130 Up 4.6667(-0.0661~9.3995) 1.0536(0.4771-1.63)

[0721] MT-TD 0.139 Up 3.2917(0.1208-6.4626) 0.8929(0.2276-1.5581)

[0722] FZD90.143 Up 2.0833(0.1267-4.04) 0.6429(0.4297-0.8561)

[0723] UCA1 0.150 Up 17.4583(8.6633-26.2534) 8.2857(-1.0225~17.5939) HIST1H2BF 0.153 Up 3.2917(-0.8671~7.4504) 0.3214(0.1512-0.4916) AC005307.1 0.155 Up 2.125(-0.1956-4.4456) 0.4643(0.1894-0.7391) AC105460.1 0.155 Up 13.5(-5.4592~32.4592) 0.0357(-0.0144~0.0859) SLC5A80.157 Up 2.75(0.7802-4.7198) 1.3214(0.8587-1.7842) AC104823.1 0.166 Up 10.125(-2.9348~23.1848) 1.0536(-0.1292-2.2363) ALPG 0.186 Up 7.5417(-2.2241~17.3074) 1.0893(0.5363-1.6423)

[0724] SPDYE160.222 Up 1.1667(-0.155-2.4884) 0.3571(0.1632-0.5511)

[0725] DCDC20.233 Up 5.7083(2.7264-8.6902) 3.7321(2.2091-5.2552)

[0726] CYP2W1 0.236 Up 50.7917(-25.9813-127.5646) 5.5893(2.9734-8.2051) ATG9B 0.292 Up 6.1667(L 1756-11.1578) 3.4821 (2.2095-4.7547)

[0727]

[0728] Table 48: List C2-1 of t-test Results for comparison between HG. AP vs healthy (only with ncRNA without protein coding)

[0729]

[0730] GAS50.002 Up 260.25(169.8631-350.6369) 99.3214(68.5237-130.1191) LNCTAM34A 0.002 Up 6.5417(4.3143-8.769) 2.5536(1.7239-3.3832) VPS9D1-AS1 0.002 Up 5.6667(3.1372-8.1962) 1.25(0.6303-1.8697) RPL10P13 0.002 Up 1.8333(1.059-2.6076) 0.4643(0.1942-0.7343) LINC009700.002 Up 2.875(1.47-4.28) 0.4643(0.1942-0.7343) AC239800.20.002 Up 5.5(3.1506-7.8494) 1.4286(0.763-2.0941) TFAP2A-AS1 0.002 Up 2.8333(1.3777-4.289) 0.3571(0.132-0.5822) AC009005.1 0.002 Up 2.8333(1.5717-4.095) 0.6786(0.4031-0.9541) AC099792.1 0.002 Up 3.4583(1.7375-5.1791) 0.5536(0.2837-0.8234) LINC011860.002 Up 3.5(1.8481-5.1519) 0.7321(0.4237-1.0406) SNRPEP20.002 Up 3.5(2.1705-4.8295) 1.2143(0.7306-1.698) AP005271.1 0.002 Up 1.375(0.7066-2.0434) 0.25(0.0713-0.4287) AC107075.1 0.002 Up 8.3333(5.0799-11.5867) 2.8214(1.8141-3.8288) AC090371.20.002 Up 1.75(0.8586-2.6414) 0.2679(0.0947-0.441) FIRRE 0.002 Up 9(4.7335-13.2665) 1.9643(1.4215-2.5071)

[0731] RPL12P40.003 Up 32.125(19.5023-44.7477) 10.8929(6.6218-15.1639) LINC008530.003 Up 2.1667(1.3252-3.0081) 0.75(0.46-1.04) RPS7P100.003 Up 105.3333(64.3566-146.3101) 36.875(23.4319-50.3181) AC036176.30.003 Up 4.6667(2.9249-6.4084) 1.6429(0.7801-2.5056) SNORA74D 0.003 Up 3.75(2.2441-5.2559) 1.2679(0.8271-1.7086) LINC018070.003 Up 3.375(1.3834-5.3666) 0.1786(-0.0063~0.3635) RPS4XP11 0.003 Up 69.125(42.6343-95.6157) 25.25(16.0595-34.4405) AC007342.40.003 Up 2.0833(1.1522-3.0145) 0.5714(0.3439-0.799) AC093866.1 0.003 Up 22.1667(9.5186-34.8148) 1.9821(0.6958-3.2685) MIR16-20.003 Up 5.25(3.1507-7.3493) 1.7679(0.9685-2.5672) CRUDE 0.003 Up 51(28.4625-73.5375) 14.2321(6.7196-21.7447) AC016712.1 0.003 Up 5.2917(3.1915-7.3919) 1.8929(1.2681-2.5176) GAPLINC 0.004 Up 4.2917(2.4054-6.1779) 1.25(0.6808-1.8192) LINC017300.004 Up 4.8333(2.7923-6.8743) 1.625(1.2211-2.0289) CYP4A22-AS1 0.004 Up 1.5(0.8411-2.1589) 0.4464(0.2364-0.6565) AL606537.1 0.004 Up 4.6667(2.8984-6.4349) 1.75(0.9601-2.5399) SNORA33 0.004 Up 4.875(2.5279-7.2221) 1.1964(0.6746-1.7183) AC016735.1 0.004 Up 1.7917(1.0345-2.5489) 0.5893(0.3351-0.8435) TDGF1P30.004 Up 5.625(2.8748-8.3752) 1.375(0.8028-1.9472) AL391056.1 0.004 Up 6.9583(3.7245-10.1922) 1.9643(1.3024-2.6261) SNORD83A 0.005 Up 2.5417(1.1004-3.983) 0.3393(0.121-0.5576) LINC022530.005 Up 6.2083(2.5589-9.8578) 0.6071 (-0.1306-1.3449) LINC022540.005 Up 12.4167(5.086-19.7473) 1.2679(0.3077-2.228) BBOX1-AS1 0.005 Up 4.4167(2.0185-6.8148) 0.75(0.3012-1.1988) ELFN1-AS1 0.005 Up 6.3333(3.1693-9.4973) 1.4643(0.7155-2.213) LINC024180.005 Up 16.375(6.5761-26.1739) 1.5536(0.3993-2.7079) SNRPGP20.005 Up 21.75(12.6199-30.8801) 7.4464(3.9062-10.9867) SHANK2-AS1 0.006 Up 2.2917(1.4158-3.1675) 0.8929(0.4635-1.3222) GHET1 0.006 Up 0.9583(0.5012-1.4155) 0.2679(0.1377-0.398) AC007608.20.006 Up 1.4583(0.5693-2.3474) 0.1429(0.0134-0.2723) AP005233.20.006 Up 12.9167(7.3218-18.5116) 4.4464(2.7535-6.1393) RPL39P3 0.006 Up 15.5833(9.3438-21.8228) 5.9464(3.4434-8.4495) LINC017480.006 Up 15.2917(7.0957-23.4877) 3.2679(1.9416-4.5941) AC022101.1 0.006 Up 13.4167(7.7488-19.0845) 5.0179(3.54-6.4957) AL161431.1 0.007 Up 6.3333(3.3432-9.3235) 1.5893(0.0105-3.1681) SNORD460.007 Up 4.6667(2.215-7.1183) 1.0536(0.442-1.6651) NPSR1-AS1 0.007 Up 7.625(3.0945-12.1555) 0.9821(-0.0257~1.99) EIF1AXP1 0.007 Up 9.25(4.9758-13.5242) 2.9107(1.6226-4.1989) LINC01811 0.007 Up 4.4583(1.9805-6.9362) 0.8571(0.3963-1.318) RPL34P180.007 Up 39.4583(25.2147-53.702) 17.4107(10.637-24.1844) AC090498.1 0.007 Up 13.0417(6.8941-19.1893) 4.0536(2.375-5.7322) HSPD1P1 0.007 Up 2.2083(1.0404-3.3763) 0.5179(0.2525-0.7832) KRT18P130.008 Up 35.625(19.6721-51.5779) 12.4286(7.0852-17.7719) AC020656.20.008 Up 15.8333(9.8985-21.7681) 6.8214(3.8793-9.7635) LINC025420.008 Up 3.5417(1.8119-5.2714) 1.0893(0.7236-1.455) AC009065.50.009 Up 5.625(3.0226-8.2274) 1.9107(1.1562-2.6652) EEF1B2P60.009 Up 72.5417(46.1029-98.9804) 32.6429(19.4712-45.8145) RPL30P40.009 Up 23.2917(14.0777-32.5056) 9.7679(5.8489-13.6868) SCARNA220.009 Up 25.6667(11.7899-39.5435) 6.375(4.2274-8.5226) IGHGP 0.009 Up 233.9167(112.3173-355.516) 61.1607(24.0905-98.2309) AC104088.20.009 Up 2.2917(1.2538-3.3296) 0.8214(0.5062-1.1367) LINC016300.009 Up 2.5(0.8109-4.1891) 0.1786(0.0632-0.294) AF064858.1 0.009 Up 7.75(4.4292-11.0708) 3.0536(2.0601-4.047) AC007608.1 0.010 Up 9.9583(4.768-15.1487) 2.6964(1.3396-4.0533) AC008481.1 0.010 Up 1.25(0.7181-1.7819) 0.4821(0.2655-0.6988) AC144450.1 0.010 Up 1.5417(0.6882-2.3951) 0.3571(0.1439-0.5703) AL590438.1 0.010 Up 2.7917(1.5098-4.0735) 1(0.6282-1.3718)

[0732] FSIP2-AS20.011 Up 3.5833(2.2312-4.9355) 1.625(0.9881-2.2619) MIR3142HG 0.012 Up 37.3333(19.6606-55.0061) 13.0179(7.3057-18.73) RPL26P190.012 Up 41.4167(22.6189-60.2144) 15.875(10.1986-21.5514) LINC026570.012 Up 1.5833(0.669-2.4976) 0.3571(0.132-0.5822) AC120349.1 0.013 Up 3.3333(1.7898-4.8769) 1.2321(0.724-1.7402) FEZF1-AS1 0.013 Up 11.2917(3.8847-18.6987) 1.5357(0.6025-2.469) AC104088.3 0.013 Up 4.1667(2.0769-6.2565) 1.3571(0.7875-1.9268) LINC001140.014 Up 4.5833(2.3877-6.7789) 1.6964(1.1257-2.2672) SNORA80B 0.014 Up 2.375(0.7813-3.9687) 0.3214(0.1437-0.4991) LINC01411 0.014 Up 8.2917(2.2999-14.2834) 0.6071(0.2545-0.9598) PURPL 0.015 Up 5.9583(2.3484-9.5683) 1.3393(0.7091-1.9695) RPL5P340.016 Up 72.0833(42.4642-101.7025) 32.3036(20.1244-44.4828) AL031710.20.016 Up 1.6667(0.763-2.5703) 0.5(0.2551-0.7449) SNRPEP40.016 Up 5.4583(2.3132-8.6035) 1.4107(0.5688-2.2526) AL441963.1 0.017 Up 2.125(0.9417-3.3083) 0.625(0.3879-0.8621) RNU5F-1 0.017 Up 5.6667(1.8721-9.4612) 0.9286(0.4081-1.449) PTPRD-AS1 0.018 Up 7.4583(4.0506-10.8661) 3.0714(1.9263-4.2166) TBCAP1 0.018 Up 8.75(4.5712-12.9288) 3.375(1.9256-4.8244) RBM8B 0.019 Up 4.75(2.8606-6.6394) 2.2143(1.2579-3.1707) AC007608.40.019 Up 57(25.8039-88.1961) 17.4107(7.2275-27.5939) EIF3FP30.020 Up 4.5833(2.4889-6.6778) 1.875(1.0083-2.7417) AC002057.20.020 Up 1.6667(0.6809-2.6524) 0.4464(0.1915-0.7014) AC010547.20.022 Up 1.9583(0.4668-3.4499) 0.1786(0.0332-0.324) H3F3AP40.023 Up 14.7083(6.9516-22.465) 5.25(2.9569-7.5431) GAS6-AS1 0.023 Up 18.2083(8.7139-27.7028) 6.875(5.0063-8.7437) YTHDF2P1 0.023 Up 1.9583(0.8413-3.0754) 0.625(0.3879-0.8621) AL354743.20.024 Up 1.4167(0.383-2.4504) 0.1964(0.0239-0.369) AC093424.1 0.025 Up 1.7917(0.7426-2.8407) 0.5536(0.3091-0.7981) AL606807.1 0.026 Up 1.375(0.4874-2.2626) 0.3393(0.1532-0.5254) SETD6P1 0.027 Up 1.4167(0.6601-2.1732) 0.5179(0.2784-0.7573) AL589669.1 0.027 Up 7.8333(3.2894-12.3773) 2.5536(1.553-3.5542) NME2P1 0.028 Up 9.375(4.4195-14.3305) 3.4643(1.6982-5.2303) CASC80.028 Up 4.8333(1.6767-7.99) 1.1607(0.3749-1.9465)

[0733] PPIAP220.028 Up 12.875(5.6515-20.0985) 4.4107(2.3365-6.485) RPL17P360.028 Up 18.25(8.3023-28.1977) 6.4821(3.1287-9.8355) LINC024890.029 Up 4.2917(1.4977-7.0857) 1.1071(0.6513-1.563) AC004034.1 0.029 Up 1.7083(0.5706-2.846) 0.4107(0.1779-0.6435) LINC018190.030 Up 24.75(4.3088-45.1912) 1.8571(0.8598-2.8545) SNORA80E 0.031 Up 3.625(1.2175-6.0325) 0.9107(0.4175-1.4039) AC004080.1 0.032 Up 2.9167(0.7459-5.0874) 0.5(0.1894-0.8106) AC007493.1 0.034 Up 2.7917(0.7956-4.7878) 0.5357(-0.0917~1.1632) AL138885.3 0.036 Up 4.5833(2.0045-7.1622) 1.6071(0.5004-2.7139) AL133297.20.038 Up 2.5417(0.7941-4.2893) 0.6607(0.3844-0.937) AC002367.1 0.040 Up 0.875(0.1672-1.5828) 0.125(0.0356-0.2144) AL359075.1 0.043 Up 1.7083(0.3247-3.092) 0.2679(0.1024-0.4333) SNORD3A 0.045 Up 192.4583(20.1566-364.7601) 15.25(3.7409-26.7591) AC078993.1 0.046 Up 21.2917(4.3642-38.2191) 3.9107(1.625-6.1964) LINC016590.050 Up 4.2083(1.9533-6.4634) 1.8929(1.3181-2.4676)

[0734]

[0735] Table 49: List C2-2 of t-test Results for comparison between HG. AP vs healthy (only with protein coding)

[0736]

[0737] IQANK1 1.50e-05 Up 41.1667(29.777-52.5563) 11.0179(8.0667-13.969)

[0738] HES6 1.53e-05 Up 172.9583(129.2111-216.7056) 56.7857(42.2802-71.2913) SAPCD2 1.58e-05 Up 79.2083(59.1481-99.2686) 26.125(19.8459-32.4041) PFDN4 1.91e-05 Up 133.7917(101.1728-166.4105) 48.7857(39.369-58.2024) ECT2 2.08e-05 Up 117(85.3679~148.6321) 35.0357(25.7016~44.3698)

[0739] RAB15 2.22e-05 Up 72.1667(54.0123-90.3211) 25.4464(20.7244-30.1685) BACE22.23e-05 Up 422.75(307.2902-538.2098) 125.5357(94.6866-156.3848) MDFI 2.58e-05 Up 3.5833(2.4842-4.6825) 0.7857(0.4981-1.0733)

[0740] AXIN22.63e-05 Up 349.4167(241.5513-457.2821) 75.75(51.6046-99.8954)

[0741] SP5 2.64e-05 Up 24.7917(16.7672-32.8161) 4.4464(2.7574-6.1355)

[0742] LIPG 2.68e-05 Up 82.5833(59.4574-105.7093) 23.8929(17.9596-29.8261) CDCA72.84e-05 Up 245.1667(186.4397-303.8936) 94.2321(69.5077-118.9566) LGR5 3.39e-05 Up 176.6667(117.4491-235.8842) 29.0536(14.035-44.0721) CSE1L 3.62e-05 Up 144.3333(107.2572-181.4095) 52.1964(41.804-62.5889) GRIN2D 3.77e-05 Up 22.8333(14.9015-30.7651) 3.2857(1.8416-4.7299) BLACAT1 3.96e-05 Up 9.4167(5.9706-12.8627) 0.9643(0.4411-1.4875)

[0743] C2 4.14e-05 Up 44.5(30.6627~58.3373) 10.4107(6.2828~14.5386)

[0744] CKAP24.15e-05 Up 97.25(71.1099-123.3901) 32.6964(24.1583-41.2345)

[0745] CKS24.41e-05 Up 205.3333(145.1624-265.5042) 57.7321(39.4376-76.0266) PPM1H 4.48e-05 Up 33.7917(23.8216-43.7617) 9.4464(6.8221-12.0708)

[0746] TGFBI 4.50e-05 Up 580.875(406.6229-755.1271) 155.4643(109.1406-201.788) HOXA94.78e-05 Up 199.625(150.0846-249.1654) 77.5(57.9288-97.0712)

[0747] ETS25.00e-05 Up 921.5(693.1834-1149.8166) 361.5(274.0043-448.9957) LINC011245.04e-05 Up 2.625(1.8903-3.3597) 0.8214(0.5321-1.1108)

[0748] SLC7A5 5.51e-05 Up 27.625(19.5959-35.6541) 8.3036(6.0479-10.5592) MAD2L1 5.64e-05 Up 110.875(79.6277-142.1223) 35.7143(26.4663-44.9623) CYP39A1 6.37e-05 Up 18.0417(13.0245-23.0588) 6.0536(4.4279-7.6793) HMGA1 6.53e-05 Up 479.1667(351.3735-606.9599) 175(135.8741-214.1259) RAD54B 6.81e-05 Up 15.6667(11.5752-19.7581) 5.9821(4.8249-7.1394) PROX1 7.09e-05 Up 106.4583(74.2829-138.6338) 30.4286(20.8436-40.0135) JPH1 7.16e-05 Up 45.5833(31.9966-59.1701) 13.5893(9.9435-17.2351)

[0749] CLDN1 7.28e-05 Up 106.4167(77.0958-135.7375) 28.25(5.4956-51.0044) TNFSF157.30e-05 Up 33.75(24.9556-42.5444) 12.9107(9.8963-15.9251) ZC3HAV1L 7.66e-05 Up 1.7917(1.2079-2.3754) 0.4107(0.2015-0.6199)

[0750] EFNA3 7.80e-05 Up 36.625(24.6856-48.5644) 8.7857(6.0486-11.5228)

[0751] RNF43 7.90e-05 Up 154.7083(109.8102-199.6065) 48.9821(33.6021-64.3622) ZNF7928.00e-05 Up 11.7083(8.0706-15.3461) 3.2321(2.3301-4.1342)

[0752] UBE2C 8.92e-05 Up 144.6667(99.1987-190.1346) 39.6607(28.4022-50.9192) MARCKSL1 9.56e-05 Up 977.9167(706.7474-1249.0859) 348.3929(253.661-443.1247) C2CD4A 9.83e-05 Up 58.2083(35.4463-80.9704) 6.375(3.1864-9.5636)

[0753] MELK 1.05e-04 Up 55.375(38.7436-72.0064) 17.1964(11.8794-22.5135)

[0754] NXT1 1.06e-04 Up 41.4167(30.1205-52.7129) 15.4107(11.4521-19.3693) CEMIP 1.08e-04 Up 120.4167(78.4421-162.3912) 24.8929(13.8857-35.9) EEF1AKMT4 1.10e-04 Up 17.3333(12.4713-22.1954) 6.2143(4.6422-7.7864) EPOP 1.15e-04 Up 14.7917(9.3626-20.2207) 2.5714(1.604-3.5388)

[0755] STMN1 1.17e-04 Up 347.3333(247.5033-447.1634) 120.9464(91.761-150.1319) KIF18A 1.22e-04 Up 26.0417(18.299-33.7844) 8.5714(6.4267-10.7162)

[0756] TOP2A 1.24e-04 Up 360.0417(256.4792-463.6041) 124.9107(89.8503-159.9711) SKA3 1.28e-04 Up 29(20.8395-37.1605) 10.5179(7.7278-13.3079)

[0757] PLEKHS1 1.28e-04 Up 94(66.1354-121.8646) 31.0536(22.0347-40.0724) NCOA7 1.32e-04 Up 215.5417(154.5381-276.5452) 79.3393(65.0914-93.5871) DACH1 1.35e-04 Up 144.0417(100.8229-187.2605) 47.7679(37.8246-57.7111) KIF4A 1.37e-04 Up 34.8333(24.7353-44.9314) 12.0357(8.4135-15.6579) ACBD7 1.40e-04 Up 6.2083(4.3241-8.0926) 1.9821(1.3683-2.596)

[0758] NEK2 1.53e-04 Up 49.375(33.3499-65.4001) 13.8571(9.2777-18.4366)

[0759] FGFRL1 1.56e-04 Up 91.4583(63.6157-119.301) 29.8393(21.7424-37.9362) MZT1 1.58e-04 Up 101.5833(71.8837-131.283) 35.9464(27.4982-44.3946) NPM1 1.59e-04 Up 654.7917(472.3628-837.2206) 250.5714(193.5916-307.5512) GPX2 1.76e-04 Up 739.1667(528.122-950.2113) 275.2143(208.1434-342.2852) BUB1 1.78e-04 Up 48.9167(33.7612-64.0721) 15.6071(10.713-20.5013) ITGA6 1.78e-04 Up 1163.25(833.8964-1492.6036) 439.5714(332.9796-546.1633) PRKDC 1.79e-04 Up 361.4167(261.1429-461.6904) 140.7857(107.3224-174.2491) MEST 1.81e-04 Up 64.9583(45.33-84.5867) 21.6071(14.4027-28.8116) MTHFD1L 1.93e-04 Up 65.5(45.3226-85.6774) 21.5179(15.1929-27.8428) SMKR1 1.93e-04 Up 3.7083(2.2697-5.1469) 0.5893(0.2011-0.9775)

[0760] MND1 1.94e-04 Up 28.3333(19.7482-36.9185) 9.5893(6.752-12.4265) PLEKHB1 2.16e-04 Up 18.4583(12.7102-24.2064) 6.0893(4.428-7.7506) SLC35E42.19e-04 Up 22.25(15.55-28.95) 7.7857(5.6175-9.954)

[0761] BUB1B 2.21e-04 Up 37.375(26.4664-48.2836) 13.5536(9.221-17.8862) ZNF2392.24e-04 Up 14.9167(10.1476-19.6858) 4.75(3.6604-5.8396) ZNRF3 2.29e-04 Up 104(75.3502-132.6498) 42.3393(32.9472-51.7314) ANLN 2.29e-04 Up 78.0833(50.9609-105.2058) 20.5179(15.1093-25.9265) NANOS3 2.29e-04 Up 2.2917(1.407-3.1764) 0.4107(0.2144-0.607) C19orf482.46e-04 Up 84.9167(58.9642-110.8691) 30(23.7695-36.2305) CDH3 2.70e-04 Up 68.0417(42.1788-93.9045) 13.6964(7.143-20.2498) HIST3H2A 2.71e-04 Up 32.5(21.2202-43.7798) 8.9286(6.731-11.1262) ACTL102.71e-04 Up 7.2917(5.0976-9.4857) 2.5893(1.7321-3.4465) CKAP2L 2.91e-04 Up 35.0833(24.3156-45.8511) 12.4107(8.9284-15.893) PLCB42.94e-04 Up 346.5833(255.9314-437.2352) 152.3571(113.803-190.9113) CD3EAP 2.96e-04 Up 19.375(13.348-25.402) 6.8214(5.3073-8.3356)

[0762] TTK 3.12e-04 Up 44.8333(31.3114-58.3553) 16.4464(11.7842-21.1087) PAFAH1B3 3.18e-04 Up 41.5417(27.9949-55.0884) 13.5(10.0735-16.9265) TDGF1 3.20e-04 Up 31.8333(19.9226-43.744) 7.2143(4.2951-10.1335) SLC28A3 3.21e-04 Up 32.5833(19.5565-45.6102) 5.8393(3.6806-7.9979) EXO1 3.23e-04 Up 20.0417(13.346-26.7373) 6.125(4.117-8.133)

[0763] KIF24 3.40e-04 Up 5.875(4.0692-7.6808) 2.1071(1.4679-2.7464)

[0764] ETV43.46e-04 Up 56.8333(32.2925-81.3741) 6.9286(3.9689-9.8882) RACGAP1 3.46e-04 Up 69.1667(47.271-91.0623) 23.8036(16.7886-30.8185) ERCC6L 3.52e-04 Up 11.9167(7.787-16.0463) 3.4821(2.6065-4.3578) RCN1 3.59e-04 Up 132.625(91.2616-173.9884) 46.7679(32.1842-61.3515) CDK1 3.71e-04 Up 115.1667(76.3527-153.9807) 35.8393(25.4883-46.1903) CDCA4 3.83e-04 Up 34.8333(23.5428-46.1239) 11.9107(9.2698-14.5516) SLCO5A1 4.06e-04 Up 11.7917(8.1507-15.4326) 4.375(3.2613-5.4887) ASCL24.30e-04 Up 230.75(144.3494-317.1506) 55.9107(30.2152-81.6063) SH3TC24.34e-04 Up 9.625(6.2176-13.0324) 2.7321(1.7063-3.7579) GPR194.36e-04 Up 2.5417(1.6353-3.448) 0.7143(0.4604-0.9682) SLCO4A1 4.41e-04 Up 64.0833(40.6481-87.5186) 17.4643(13.9962-20.9324) RNF183 4.50e-04 Up 34.8333(20.4367-49.23) 6.2857(4.525-8.0464) DBNDD1 4.59e-04 Up 3.4167(2.1908-4.6425) 0.9643(0.6496-1.2789) TRIP13 4.75e-04 Up 42.5417(26.6862-58.3971) 11.0893(7.8441-14.3345) AJUBA 4.75e-04 Up 23.2917(14.6303-31.9531) 6.0357(3.8812-8.1902) FBXO5 4.98e-04 Up 41.2917(27.526-55.0573) 14.0179(10.718-17.3178) SKA1 5.04e-04 Up 24.7083(15.9119-33.5047) 7.25(4.9315-9.5685)

[0765] CXCL3 5.29e-04 Up 342.5(201.0989-483.9011) 63.0357(25.1988-100.8727) ALKAL1 5.40e-04 Up 5.4583(3.4896~7.4271) 1.5357(0.8739~2.1976) RANBP1 5.40e-04 Up 295(201.7785-388.2215) 107.8571(72.7043-143.01) GINS1 5.51e-04 Up 55.0417(36.1655-73.9178) 18(13.4492-22.5508) NUP62CL 5.56e-04 Up 9.875(6.4893-13.2607) 3.1429(1.9914-4.2944) C2CD4B 5.59e-04 Up 32.2083(20.5228-43.8938) 9.3036(6.4507-12.1565) CDC205.63e-04 Up 83.25(57.2101-109.2899) 31.1071(21.1242-41.09) IQGAP3 5.68e-04 Up 43.9167(28.6065-59.2268) 13.875(9.8027-17.9473) KIF2C 5.81e-04 Up 39.625(26.8998-52.3502) 14.5536(10.6052-18.502) NUF25.89e-04 Up 49.7083(33.3606-66.0561) 17.5(12.3026-22.6974) HSPE1 6.12e-04 Up 758.0417(532.9982-983.0851) 309.6964(220.2548-399.1381) CCNB1 6.12e-04 Up 119.875(79.3827-160.3673) 40.5179(28.0242-53.0115) DLGAP5 6.19e-04 Up 48.2083(32.7204-63.6962) 17.625(12.0655-23.1845) CENPA 6.25e-04 Up 33.7917(22.5532-45.0301) 11.9107(8.7942-15.0272) RAN 6.47e-04 Up 721.9583(494.6361-949.2806) 277.875(204.6887-351.0613) IFITM3 6.51e-04 Up 566.7083(377.2922-756.1244) 197.1786(136.9484-257.4087) HS6ST27.05e-04 Up 16.4167(9.0197-23.8137) 2.3571(1.1493-3.565) SALL47.32e-04 Up 11.9167(7.5162-16.3172) 3.5(2.3479-4.6521)

[0766] CENPI 7.33e-04 Up 12.5417(8.2211-16.8623) 4.25(3.0072-5.4928)

[0767] FAM72D 7.41e-04 Up 3.1667(1.9876-4.3458) 0.8393(0.3241-1.3545) LRRIQ47.51e-04 Up 6.5417(3.9209-9.1624) 1.5536(0.9159-2.1912)

[0768] CCNA27.54e-04 Up 78.9167(53.2592-104.5741) 29.3571(20.5336-38.1807) C2CD4D 7.57e-04 Up 4.4583(2.9487-5.9679) 1.5357(0.9953-2.0761) LMNB28.26e-04 Up 178.7917(120.5473-237.036) 67.7143(48.8669-86.5617) KIF18B 8.48e-04 Up 37.6667(24.7493-50.584) 13.2321(9.4997-16.9646) DDIAS 8.48e-04 Up 17.75(11.896-23.604) 6.5714(4.5513-8.5916)

[0769] SLC6A68.80e-04 Up 15.25(9.5042-20.9958) 4.5179(3.2432-5.7925)

[0770] TP53 8.83e-04 Up 224.5(152.613-296.387) 88.6786(66.5203-110.8369) CDKN3 8.96e-04 Up 79.9583(52.9819-106.9348) 28.9464(20.2659-37.627) CELSR3 9.42e-04 Up 13.8333(8.875-18.7917) 4.5893(3.2855-5.893)

[0771] EGFL69.64e-04 Up 4.5833(2.5376-6.6291) 0.7857(0.2758-1.2957)

[0772] CEP55 9.67e-04 Up 56.7917(36.0228-77.5605) 17.9643(11.7263-24.2023) RASSF109.80e-04 Up 14.0833(9.2432-18.9234) 4.9286(3.1333-6.7238) TNFRSF10B 0.001 Up 57.9583(38.073-77.8437) 21.0536(15.4453-26.6618) TSACC 0.001 Up 1.2083(0.7428-1.6739) 0.3393(0.1756-0.503)

[0773] E2F70.001 Up 14.5(8.7749-20.2251) 4.0714(3.0263-5.1166)

[0774] LRP40.001 Up 91.5(59.1894-123.8106) 31.4464(20.6421-42.2507)

[0775] CDC60.001 Up 48.3333(29.8141-66.8526) 14.6786(10.6529-18.7042) PSAT1 0.001 Up 57.9583(33.1946-82.722) 13.1429(8.5694-17.7163) KPNA20.001 Up 184.625(111.1257-258.1243) 50.9821(33.9668-67.9975) CYP19A1 0.001 Up 1.5833(0.9744-2.1923) 0.4643(0.2667-0.6618)

[0776] RRM20.001 Up 237.125(145.5985-328.6515) 71.5(51.039-91.961)

[0777] EPHB30.001 Up 153.1667(96.0411-210.2923) 49.25(33.7142-64.7858) CADPS 0.001 Up 61.5417(38.5219-84.5614) 20.125(15.1872-25.0628) INHBA 0.001 Up 63.0417(37.5709-88.5125) 16.4286(7.9262-24.931)

[0778] STC20.001 Up 16.0833(8.9488-23.2178) 3.3036(1.8484-4.7587)

[0779] IP040.001 Up 5.25(3.3979-7.1021) 1.8929(1.3484-2.4373)

[0780] GRIN2B 0.001 Up 34(18.9245-49.0755) 6.75(2.4642-11.0358)

[0781] E2F1 0.001 Up 25.4167(16.4065-34.4268) 9.0357(6.0738-11.9976)

[0782] LGR60.001 Up 23.0417(14.3214-31.7619) 7.4464(5.4647-9.4282)

[0783] SORD 0.001 Up 25.9167(15.1677-36.6657) 6.7143(4.1025-9.3261)

[0784] XKRX 0.001 Up 4.625(2.8517-6.3983) 1.3929(0.7516-2.0341)

[0785] C17orf770.001 Up 4.8333(2.9299-6.7367) 1.1964(0.1694-2.2234)

[0786] MEX3A 0.001 Up 26.75(16.3318-37.1682) 8.2857(6.3642-10.2072)

[0787] OPRD1 0.001 Up 4.5417(2.5378-6.5455) 1(0.677-1.323)

[0788] UBE2T 0.001 Up 85.5417(54.2835-116.7998) 29.75(20.8589-38.6411) TMEM211 0.001 Up 5(2.8041-7.1959) 1.1071(0.5603-1.654)

[0789] LINC003460.001 Up 2.7917(1.7802-3.8031) 0.9643(0.5962-1.3324) HIST1H2BL 0.002 Up 4.4167(2.3112-6.5222) 0.7321(0.3993-1.065) MMP100.002 Up 16.4583(8.9252-23.9914) 3.2321(1.7442-4.7201)

[0790] CBX20.002 Up 10(4.872-15.128) 1.1071(0.687-1.5273)

[0791] MSLN 0.002 Up 34.2083(16.2466-52.1701) 3.2143(2.0568-4.3718) CEACAM60.002 Up 1284.125(790.6455-1777.6045) 421.3036(295.5897-547.0174) CCNO 0.002 Up 26.5417(16.2089-36.8744) 8.625(6.3673-10.8827)

[0792] PHLDA1 0.002 Up 197.9583(115.3711-280.5455) 54.4464(32.7296-76.1632) CCL260.002 Up 3.0833(1.4554-4.7112) 0.3036(0.1273-0.4799)

[0793] RAD51AP20.002 Up 3.25(1.9485-4.5515) 1(0.6462-1.3538)

[0794] HOXB60.002 Up 149.5(97.7795-201.2205) 59.0357(41.458-76.6134) C11orf53 0.002 Up 9.1667(5.9444~12.3889) 3.5536(2.5009~4.6063)

[0795] GGH 0.002 Up 285.5833(188.2061-382.9606) 117.1607(88.7982-145.5232) TICRR 0.002 Up 10.625(6.672-14.578) 3.6964(2.2602-5.1326)

[0796] C6orf2230.002 Up 12.0833(6.582-17.5846) 2.6786(1.3735-3.9837)

[0797] NOX1 0.002 Up 278.8333(182.4403-375.2264) 112.1964(82.409-141.9839) TMEM132A 0.002 Up 8.2083(4.7644-11.6523) 2.2679(1.2345-3.3013) C3orf670.002 Up 7.625(4.8412-10.4088) 2.7321(1.6339-3.8304)

[0798] TNFRSF11B 0.002 Up 33.625(20.0955~47.1545) 10.5179(7.2265~13.8093) KIAA12570.002 Up 8.5417(5.0619-12.0215) 2.625(1.8822-3.3678) UHRF1 0.002 Up 58.375(33.7081-83.0419) 16.5714(11.4374-21.7054) TEX450.002 Up 5.4583(3.3197-7.5969) 1.7857(1.0973-2.4741)

[0799] RUBCNL 0.002 Up 107.5417(70.3244-144.759) 43.1786(29.4985-56.8587) PIMREG 0.002 Up 16.5(10.2294-22.7706) 5.8036(3.9248-7.6823)

[0800] OXGR1 0.002 Up 15.7083(8.4397-22.9769) 3.5536(2.4886-4.6186)

[0801] C2orf700.002 Up 5.8333(3.4039-8.2628) 1.6964(0.978-2.4149)

[0802] EDAR 0.002 Up 11.9583(6.5243~17.3924) 2.8929(2~3.7857)

[0803] SNRPG 0.002 Up 243.4167(154.819-332.0143) 92.0536(59.8856-124.2215) CDCA20.002 Up 27.2083(16.4413-37.9754) 9.1964(6.3954-11.9974)

[0804] TUBB5 0.003 Up 715.25(445.7394~984.7606) 262.9286(185.7988~340.0583) RPL22L1 0.003 Up 406.5417(212.42-600.6633) 87.3036(64.3338-110.2733) ODC1 0.003 Up 317.5417(177.2042-457.8792) 86.4286(65.3985-107.4586) TG 0.003 Up 2.5(1.4289-3.5711) 0.7143(0.3845-1.0441)

[0805] CCL200.003 Up 261.125(134.0371-388.2129) 52.9643(28.3929-77.5356) CXCL20.003 Up 121.75(62.4118-181.0882) 23.9821(8.9753-38.989) GMDS 0.003 Up 497.5(317.22-677.78) 199.5893(149.6981-249.4804) LINC015490.003 Up 1.3333(0.6002-2.0665) 0.1429(0.0354-0.2503) CHRNA50.003 Up 9.5833(5.9277-13.239) 3.5714(2.5016-4.6412)

[0806] BMP70.003 Up 28.75(16.4426-41.0574) 8.8929(6.7906-10.9951)

[0807] CPNE70.003 Up 14.4583(7.2084-21.7082) 2.8036(1.66-3.9471)

[0808] KLHL320.003 Up 8.4583(5.0054-11.9113) 2.8929(2.2336-3.5522)

[0809] PBK 0.003 Up 60.125(34.9897-85.2603) 19.5536(13.4325-25.6747)

[0810] TNS40.003 Up 80.2917(37.8101-122.7732) 12.9286(8.5717-17.2855) WDR720.003 Up 19.7083(10.1216-29.295) 4.4464(2.9576-5.9352) LINC023130.003 Up 5.4167(3.2281-7.6052) 1.8929(1.3226-2.4631) CXCL160.003 Up 47.2917(25.1254-69.4579) 12.125(8.5349-15.7151) CCDC1960.003 Up 6.4583(4.109-8.8077) 2.5536(1.5634-3.5437) SERPINB50.004 Up 124.9583(68.3623-181.5544) 31.5357(9.0216-54.0498) FAM167A 0.004 Up 7.2083(4.5817-9.835) 2.875(1.8086-3.9414)

[0811] YBX1 0.004 Up 600.4167(393.272-807.5613) 257.4464(169.6706-345.2222) CYP4X1 0.004 Up 41.875(21.0702-62.6798) 9.25(6.1931-12.3069) ATP6V1C20.004 Up 7.0833(3.8413-10.3254) 1.9107(0.932-2.8894) MSX20.004 Up 40.1667(18.4034-61.9299) 6.1607(2.7048-9.6167)

[0812] MMP3 0.004 Up 90.9583(43.0937-138.823) 16.2143(6.2617-26.1668) ZNF6950.004 Up 2.25(1.1345-3.3655) 0.5179(0.3201-0.7156)

[0813] PDZK1IP1 0.004 Up 175.2083(93.9165-256.5002) 49.5179(35.0716-63.9641) ACAN 0.004 Up 4.9167(2.4359-7.3974) 1.0536(0.4314-1.6757)

[0814] PLAGL20.005 Up 82.25(48.0978-116.4022) 30.1071(24.3624-35.8519) TRMT1120.005 Up 157.3333(94.5511-220.1156) 59.5714(39.9871-79.1558) GNL30.005 Up 86.3333(52.7298-119.9369) 33.9643(23.1205-44.8081) CBX80.005 Up 19.375(10.7178-28.0322) 6.25(4.8401-7.6599)

[0815] CDC450.005 Up 22.6667(11.8876-33.4457) 6.1786(3.6205-8.7366) TNFSF90.005 Up 11.3333(4.9056-17.761) 1.6429(0.9475-2.3383)

[0816] GZMB 0.005 Up 9.75(5.3016-14.1984) 2.9821(1.9717-3.9926)

[0817] OR2I1P 0.005 Up 3.6667(1.7551-5.5782) 0.7679(0.3723-1.1634)

[0818] REG40.005 Up 1663.5(869.7988-2457.2012) 414.3393(94.5524-734.1262) TLX1 0.005 Up 3.9583(2.2534-5.6633) 1.3571(0.9136-1.8007)

[0819] KIF20A 0.005 Up 25.5833(14.281-36.8857) 8.375(5.5484-11.2016)

[0820] GAPDH 0.005 Up 3.6667(2.0591-5.2742) 1.2143(0.7415-1.6871)

[0821] FGGY 0.006 Up 61.625(30.4357-92.8143) 15.25(11.5858-18.9142)

[0822] WNT20.006 Up 6.8333(2.9439-10.7228) 1.0536(0.3714-1.7357)

[0823] C1QBP 0.006 Up 132.5417(72.9758-192.1075) 42.0893(22.7299-61.4487) ASF1B 0.006 Up 41.5833(24.0112~59.1554) 15.0179(9.5575~20.4782) CLDN20.006 Up 107.9167(47.8281-168.0052) 19.0893(8.8728-29.3058) LINC002390.006 Up 2.4583(1.3105-3.6062) 0.75(0.4884-1.0116) SERPINA1 0.006 Up 610.0417(300.1898-919.8935) 154.1786(107.5009-200.8563) PLEKHG40.006 Up 20.2083(12.064-28.3526) 7.75(4.6786-10.8214) TP53I11 0.006 Up 54.125(33.7826-74.4674) 22.7857(14.4677-31.1038) KLK120.006 Up 11.0417(4.6748-17.4085) 1.7143(0.8272-2.6013) AC027808.20.006 Up 1.625(0.9009-2.3491) 0.5(0.177-0.823) NPFFR1 0.006 Up 5.5417(2.6482-8.4352) 1.3036(0.8645-1.7426)

[0824] KLK100.006 Up 18.3333(8.6475-28.0191) 4.0893(2.1845-5.9941)

[0825] TRIB30.006 Up 35.2083(17.5587-52.8579) 9.3214(6.1143-12.5286)

[0826] APIP 0.006 Up 127.7917(73.1824-182.401) 46.3571(29.8066-62.9077) OLFM4 0.007 Up 5522.6667(2328.0238-8717.3096) 902.4286(550.5311-1254.326) CCDC1920.007 Up 3.0833(1.7543-4.4123) 1.1071(0.6839-1.5304)

[0827] L1TD1 0.007 Up 275(133.1381-416.8619) 66.4464(27.6952-105.1976) HSF1 0.007 Up 11.625(7.3917-15.8583) 4.9107(2.5664-7.255)

[0828] EVX1 0.007 Up 5.9167(2.4037-9.4296) 0.8571(0.3769-1.3374)

[0829] HIST1H4I 0.007 Up 6.7917(3.7749-9.8085) 2.2679(1.0905-3.4452)

[0830] APEX1 0.008 Up 113.125(69.2304-157.0196) 48.3214(32.9462-63.6967) LY6G6F-LY6G6D 0.008 Up 76.375(27.0173-125.7327) 6.3571(2.7688-9.9455) PCSK1 0.008 Up 94.875(35.1118-154.6382) 10.5714(8.1578-12.9851) AL590708.1 0.008 Up 4.75(2.5996-6.9004) 1.6607(1.1468-2.1746)

[0831] KLF160.008 Up 14.625(8.5736-20.6764) 5.6964(3.4495-7.9434)

[0832] IER30.008 Up 12.75(6.5387-18.9613) 3.9286(2.9112-4.9459)

[0833] ASS1 0.008 Up 239(131.7133-346.2867) 85.2857(60.1362-110.4353) GMPR 0.008 Up 19.7083(10.1087-29.308) 5.9821(3.7118-8.2525)

[0834] RPSA 0.008 Up 393.75(233.1-554.4) 156.4286(92.8064-220.0508)

[0835] TEDC20.008 Up 5.2917(2.7022-7.8812) 1.5714(0.8459-2.297)

[0836] RPL18A 0.008 Up 726.8333(423.4265-1030.2402) 284.4107(177.3784-391.443) MSX1 0.008 Up 46.9583(19.7094-74.2073) 8.7143(5.4705-11.9581) EPHA20.008 Up 89.25(42.8862-135.6138) 24.1964(18.3695-30.0234) PDCD2L 0.009 Up 13.875(7.3853-20.3647) 4.5893(2.678-6.5006) DMRTA20.009 Up 5.7083(2.0515-9.3652) 0.6071(0.0723-1.142)

[0837] HSPA80.009 Up 433.6667(244.1923-623.1411) 158.1607(86.2441-230.0774) LRRC360.009 Up 5.625(2.9347-8.3153) 1.8393(1.1999-2.4787)

[0838] CHST40.009 Up 3.5417(1.1857-5.8976) 0.2857(0.0966-0.4748)

[0839] S100P 0.009 Up 967.9583(547.8284-1388.0883) 360.3571(200.8299-519.8844) PCSK90.009 Up 41.9167(22.3415-61.4918) 13.9107(7.1562-20.6652) PAX90.009 Up 5.5(2.8178-8.1822) 1.7143(0.942-2.4866)

[0840] GDF150.010 Up 232.4167(86.1585-378.6749) 32.1786(22.3441-42.0131) MAP1S 0.010 Up 13.75(7.6546-19.8454) 5.1071(3.0634-7.1509)

[0841] MMP70.010 Up 82.5417(31.5634-133.52) 12.4821(3.505-21.4593) MRPL490.010 Up 21.7917(13.2742-30.3091) 9.3214(5.2661-13.3768) U2AF20.010 Up 45.0417(25.3168-64.7666) 17.5357(11.7358-23.3357) MELTF 0.010 Up 63.75(30.7499-96.7501) 18.7321(13.4063-24.058)

[0842] OTX1 0.011 Up 4.2917(1.5622-7.0211) 0.6071(0.1428-1.0715)

[0843] SLC35D3 0.011 Up 4.375(1.4368-7.3132) 0.4643(0.2876-0.6409)

[0844] PLK1 0.012 Up 34.5833(19.0864-50.0802) 13.1786(7.9-18.4571)

[0845] PKM 0.012 Up 411.3333(193.3667-629.3) 119.6786(84.1654-155.1918) XKR90.012 Up 10.0833(6.0737-14.093) 4.4821(2.9214-6.0428)

[0846] SMN1 0.012 Up 6.375(3.5035-9.2465) 2.5179(1.8404-3.1953)

[0847] IFI60.012 Up 347.25(138.2734-556.2266) 71.7679(51.0182-92.5175) SH3BGRL30.012 Up 22.0833(10.8133-33.3534) 6.8036(3.3895-10.2176) PGAM1 0.012 Up 21.9583(11.7619-32.1548) 8.2857(5.7556-10.8159) HPDL 0.012 Up 24.2083(14.2197-34.197) 10.4643(6.7779-14.1507) SLC7A11 0.013 Up 79.4583(33.9039-125.0127) 20.1607(15.2726-25.0488) MYEOV 0.013 Up 27.625(11.5636-43.6864) 6.6429(4.1134-9.1724)

[0848] 0ST40.014 Up 78.2917(42.5057-114.0776) 29.5(15.7602-43.2398)

[0849] IGFL40.014 Up 1.7917(0.8435-2.7398) 0.5179(0.2073-0.8285)

[0850] ULBP30.014 Up 11.9167(5.0535-18.7798) 3(2.1244-3.8756)

[0851] GPRC5A 0.014 Up 587.125(293.7799-880.4701) 206.1071(158.5611-253.6531) PKD1L30.015 Up 1.1667(0.4442-1.8892) 0.2321(0.0971-0.3672)

[0852] TRIM70.015 Up 23.9167(11.3693-36.464) 7.7143(5.453-9.9756)

[0853] POU6F20.015 Up 6.3333(2.0948-10.5718) 0.9107(0.4419-1.3795)

[0854] SPINK 40.016 Up 1025.25(544.638-1505.862) 389.4821(216.4551-562.5092) LAIR20.016 Up 4.9583(1.8994-8.0172) 1.0179(0.2596-1.7762)

[0855] CD550.016 Up 466.8333(193.526-740.1407) 121.5357(92.2342-150.8373) PRSS220.016 Up 32.875(13.7047-52.0453) 8.5893(5.6112-1 E5674) CXCL80.016 Up 109.75(39.837-179.663) 20.0357(2.9414-37.1301)

[0856] CNTD20.016 Up 8.75(2.8079-14.6921) 1.2321(0.2822-2.182)

[0857] SLCO1B30.017 Up 28.875(8.0807-49.6693) 2.8571(1.1973-4.517)

[0858] NPSR1 0.017 Up 4.8333(1.6865-7.9801) 0.7857(-0.1245-1.696)

[0859] KDELR3 0.017 Up 70.6667(35.5435-105.7899) 25.6071(15.7563-35.458) PRDX1 0.017 Up 11.625(5.5327-17.7173) 3.6607(1.3876-5.9338)

[0860] DLX60.017 Up 4.5833(1.3773-7.7893) 0.5893(0.229-0.9496)

[0861] CHI3L1 0.017 Up 19.75(10.6685-28.8315) 6.9643(1.5465-12.382)

[0862] KRT80 0.017 Up 16.375(8.3827-24.3673) 4.4643(-1.3898-10.3184)

[0863] CALR 0.017 Up 34.7083(18.8233-50.5933) 13.7679(7.1888-20.3469)

[0864] REG1B 0.018 Up 389(84.2356-693.7644) 12.8036(-3.3621-28.9692)

[0865] CACNG80.018 Up 5.1667(1.7985-8.5348) 0.9821(0.4805-1.4838)

[0866] NT5DC20.018 Up 6.625(2.5106-10.7394) 1.5(0.699-2.301)

[0867] PI30.019 Up 144.75(48.7887-240.7113) 26.875(14.6211-39.1289)

[0868] UBE2S 0.019 Up 7(2.8032-11.1968) 1.8393(1.0771-2.6015)

[0869] ACAT20.020 Up 3.4583(1.9082-5.0085) 1.4464(0.7749-2.118)

[0870] IL23A 0.021 Up 12.4167(4.2411-20.5923) 2.5(1.2872-3.7128)

[0871] TUBB4B 0.021 Up 63.3333(32.3781-94.2886) 23.8929(11.6443-36.1414) CENPN 0.021 Up 7.3333(3.6507-11.0159) 2.8214(1.979-3.6638)

[0872] LENG80.021 Up 15.9167(8.527-23.3063) 6.6607(4.1267-9.1948)

[0873] ROBO20.021 Up 12.25(5.7915-18.7085) 4.4286(3.3478-5.5093)

[0874] ESM1 0.021 Up 11.8333(3.0996-20.5671) 1.3571(0.7144-1.9999)

[0875] NKD1 0.021 Up 116.5833(50.7122-182.4545) 35.3929(16.5911-54.1946) CCDC330.021 Up 1.375(0.396-2.354) 0.1964(0.0482-0.3446)

[0876] PLP20.022 Up 5.7083(2.5669-8.8498) 1.75(0.4741-3.0259)

[0877] NOS20.022 Up 61.7917(25.4724-98.111) 17.5(7.2993-27.7007)

[0878] SIGLEC120.024 Up 2.3333(1.1028-3.5639) 0.8571(0.5168-1.1975)

[0879] ERFE 0.024 Up 4.5(1.3845-7.6155) 0.8393(0.3527-1.3258)

[0880] MCIDAS 0.025 Up 1.25(0.49-2.01) 0.3393(0.127-0.5516)

[0881] LIF 0.026 Up 15.625(5.6318-25.6182) 4.0357(2.4314-5.6401)

[0882] PLA2G30.027 Up 2.6667(0.9204-4.4129) 0.6071(0.1235-1.0907)

[0883] ZIC20.027 Up 37.6667(8.2598-67.0735) 3.8929(0.2356-7.5501)

[0884] FOXD1 0.027 Up 3.25(0.8998-5.6002) 0.5536(0.2561-0.851)

[0885] AC118754.1 0.028 Up 11.9167(3.5898-20.2435) 2.3571(0.9826-3.7316) PHLDA20.028 Up 124.625(49.0072-200.2428) 38.0357(27.1516-48.9199) TRIM720.028 Up 14.9583(3.0641-26.8526) 1.4107(0.2199-2.6016) TRMT112P60.028 Up 5.4167(2.0319-8.8015) 1.5179(0.7796-2.2561)

[0886] KLRK1 0.029 Up 3.625(1.7958-5.4542) 1.5(1.0102-1.9898)

[0887] COL11A1 0.029 Up 19.0833(4.7076-33.4591) 2.8036(1.6076-3.9995)

[0888] DUOX20.030 Up 489.7917(129.4164-850.1669) 84.0179(45.1508-122.8849) APLN 0.030 Up 9.9583(2.281-17.6357) 1.3571(0.7184-1.9959)

[0889] MORC40.030 Up 111.4583(36.8866-186.0301) 27.9464(21.1367-34.7562) ART30.031 Up 19(5.3069-32.6931) 3.7143(2.2956-5.1329)

[0890] KLK60.033 Up 8.7083(3.7378-13.6789) 2.6071(-0.079~5.2933)

[0891] AMH 0.034 Up 4.4583(1.6135-7.3032) 1.2321(0.3565-2.1078)

[0892] PRKCG 0.034 Up 3.3333(0.9393-5.7274) 0.7143(0.4656-0.963)

[0893] ASCL50.035 Up 1.4167(0.4057-2.4276) 0.3036(0.113-0.4941)

[0894] MT-ND1 0.035 Up 4708.375(2497.7141-6919.0359) 2154.4643(1270.0922-3038.8363) AC005833.1 0.035 Up 14.875(7.0995-22.6505) 6.0714(3.4766-8.6663)

[0895] FBXL160.035 Up 9.7917(3.2607-16.3226) 2.6429(1.5566-3.7291)

[0896] LINC015550.036 Up 1.75(0.5284-2.9716) 0.4107(0.1565-0.6649)

[0897] PF40.038 Up 7.625(2.9067-12.3433) 2.4821(1.3334-3.6309)

[0898] RPS250.039 Up 247.8333(119.866-375.8007) 104.7857(56.7093-152.8622) RAET1L 0.039 Up 5.7083(0.989-10.4277) 0.6964(0.1758-1.217)

[0899] SLC22A11 0.040 Up 5.2917(1.4649-9.1184) 1.1964(0.4079-1.985)

[0900] CXCL1 0.041 Up 430.5(90.8071-770.1929) 71.6429(22.9354-120.3504)

[0901] GAD1 0.041 Up 4(1.1935-6.8065) 1.0179(0.4714-1.5643)

[0902] KRT230.042 Up 18(3.7585-32.2415) 2.875(-0.2822~6.0322)

[0903] NPW 0.042 Up 9.875(2.8429-16.9071) 2.4643(1.2451-3.6835)

[0904] DHRS20.042 Up 5.4167(1.4342-9.3992) 1.2321(0.6151-1.8492)

[0905]

[0906] Table 50: List C3 of t-test Results for comparison between LG. AP vs healthy

[0907] S

[0908] P

[0909] S

[0910]

[0911] H0XB-AS4 1.08e-07 Up 31.75(27.91-35.59) 15.5357(11.2913-19.7802) AC093866.1 1.19e-07 Up 12.2969(8.9873-15.6065) 1.9821(0.6958-3.2685) ENC1 1.29e-07 Up 223.7188(193.1711-254.2664) 103.0536(72.8579-133.2493) HES6 1.29e-07 Up 119.875(102.7502-136.9998) 56.7857(42.2802-71.2913) LINC01748 1.75e-07 Up 14.1562(10.5926-17.7199) 3.2679(1.9416-4.5941) MET 1.79e-07 Up 124.3438(102.4997-146.1878) 52.875(39.7235-66.0265) BACE2 1.97e-07 Up 281.3281(234.5993-328.057) 125.5357(94.6866-156.3848) CLCA1 2.01e-07 Up 4111.2656(3236.4063-4986.1249) 1392.3929(989.2431-1795.5426) KDELC1P1 2.10e-07 Up 2.3281(1.8324-2.8238) 0.6964(0.382-1.0109)

[0912] OLFM4 2.19e-07 Up 5163.4375(3722.5127-6604.3623) 902.4286(550.5311-1254.326) TEX45 2.51e-07 Up 5.4844(4.3375-6.6312) 1.7857(1.0973-2.4741)

[0913] OXGR1 2.64e-07 Up 10.4375(8.2078-12.6672) 3.5536(2.4886-4.6186)

[0914] HOXA9 3.09e-07 Up 164.0625(138.9488-189.1762) 77.5(57.9288-97.0712) AC020891.23.18e-07 Up 1.4688(1.1156-1.8219) 0.375(0.194-0.556)

[0915] CLDN2 3.89e-07 Up 67.8438(52.9687-82.7188) 19.0893(8.8728-29.3058) GRIN2B 4.15e-07 Up 33.2969(24.566-42.0277) 6.75(2.4642-11.0358)

[0916] GAS6-AS1 4.76e-07 Up 20.375(15.803-24.947) 6.875(5.0063-8.7437) LINC008584.79e-07 Up 3.9688(2.8777-5.0598) 0.75(0.307-1.193)

[0917] CCNO 5.31e-07 Up 18.5156(15.559-21.4722) 8.625(6.3673-10.8827)

[0918] AGT 6.19e-07 Up 29.4688(23.9555-34.982) 12.625(9.5522-15.6978)

[0919] SAMD5 6.86e-07 Up 118.7656(98.7581-138.7731) 51.3571(35.2883-67.426) AC104088.3 7.45e-07 Up 4.4531(3.4315-5.4748) 1.3571(0.7875-1.9268) LRRC36 8.18e-07 Up 5.5312(4.2899-6.7726) 1.8393(1.1999-2.4787)

[0920] MYB 8.23e-07 Up 168.5625(145.5008-191.6242) 86.2857(64.6553-107.9161) NANOS3 8.25e-07 Up 1.5156(1.1459-1.8853) 0.4107(0.2144-0.607)

[0921] C17orf77 8.85e-07 Up 6.6562(4.8472-8.4653) 1.1964(0.1694-2.2234)

[0922] AC091182.29.02e-07 Up 2.6719(1.9924-3.3513) 0.6964(0.3861-1.0067) AC124067.49.08e-07 Up 12.9844(10.6011-15.3677) 5.2321(3.4368-7.0275) FZD9 9.13e-07 Up 3.1094(2.2191-3.9996) 0.6429(0.4297-0.8561)

[0923] PF4 1.12e-06 Up 11.3594(8.199-14.5198) 2.4821(1.3334-3.6309)

[0924] LINC01819 1.14e-06 Up 22.4219(14.8293-30.0145) 1.8571(0.8598-2.8545) AC099792.1 1.16e-06 Up 3.1094(2.1842-4.0346) 0.5536(0.2837-0.8234)

[0925] TRPM2-AS 1.16e-06 Up 4.7344(3.3946-6.0742) 0.9821(0.5017-1.4625) AC016735.1 1.25e-06 Up 1.8594(1.4375-2.2813) 0.5893(0.3351-0.8435) LINC01124 1.25e-06 Up 2.3594(1.8396-2.8791) 0.8214(0.5321-1.1108) AC106045.1 1.43e-06 Up 4(3.1154-4.8846) 1.2679(0.6647-1.871)

[0926] LINC02595 1.47e-06 Up 16.9531(14.3038-19.6025) 7.9643(5.6102-10.3184) CELSR3 1.49e-06 Up 9.5(8.0661-10.9339) 4.5893(3.2855-5.893)

[0927] SOX9 1.57e-06 Up 322.6875(263.6852-381.6898) 142.9107(103.9979-181.8236) LINC00920 1.62e-06 Up 11.0625(8.5857-13.5393) 3.8036(2.4074-5.1997)

[0928] FDXR 1.63e-06 Up 17.7188(14.756-20.6815) 8.6964(6.7332-10.6597)

[0929] FSIP2-AS2 1.63e-06 Up 4.4844(3.554-5.4148) 1.625(0.9881-2.2619)

[0930] TTPA 1.72e-06 Up 20.0625(16.6581-23.4669) 9.75(7.518-11.982)

[0931] RPL10P2 1.88e-06 Up 1.125(0.8119-1.4381) 0.25(0.1125-0.3875)

[0932] SERPINA1 1.91e-06 Up 529.8906(391.8701-667.9112) 154.1786(107.5009-200.8563) AC090371.2 1.95e-06 Up 1.4531(1.0241-1.8822) 0.2679(0.0947-0.441) GALNT8 2.00e-06 Up 13.6406(11.193-16.0882) 5.7857(3.8226-7.7488) IQANK1 2.07e-06 Up 23.3906(19.4241-27.3571) 11.0179(8.0667-13.969) KSR2 2.12e-06 Up 7.9688(6.5884-9.3491) 3.6964(2.6906-4.7022)

[0933] AC022075.1 2.15e-06 Up 12.3125(9.8433-14.7817) 5.3393(4.1176-6.5609)

[0934] SP5 2.30e-06 Up 13.4688(10.306-16.6315) 4.4464(2.7574-6.1355)

[0935] SEMA3F 2.64e-06 Up 19.5938(16.3749-22.8126) 10.0893(8.0198-12.1588) LINC020862.90e-06 Up 83.9219(72.3727-95.4711) 43.875(32.3659-55.3841) AC124067.3 3.27e-06 Up 10.7344(8.6787-12.79) 3.8571(1.9318-5.7825)

[0936] GAU1 3.50e-06 Up 25.3594(21.1281-29.5906) 12.0714(8.6313-15.5115)

[0937] MB 3.53e-06 Up 16.0781(13.4962-18.66) 8.1071(6.1001-10.1142)

[0938] AC007608.2 3.77e-06 Up 1.6875(1.0873-2.2877) 0.1429(0.0134-0.2723)

[0939] EGF 3.98e-06 Up 11.0781(8.8301-13.3262) 4.6071(3.1913-6.023)

[0940] ADAM32 4.03e-06 Up 6.5(5.3785-7.6215) 2.9464(1.9973-3.8955)

[0941] PCSK1 4.15e-06 Up 60.5781(40.8512-80.305) 10.5714(8.1578-12.9851) PDZK1IP1 4.22e-06 Up 133.4219(102.4217-164.422) 49.5179(35.0716-63.9641) TDGF1 4.27e-06 Up 19.9688(15.5888-24.3487) 7.2143(4.2951-10.1335) AC078883.24.62e-06 Up 66.4219(56.7704-76.0733) 33.8571(24.3267-43.3876) ATOH8 4.90e-06 Up 29.5312(23.6838-35.3787) 13.0536(9.5308-16.5763) AC027808.2 4.96e-06 Up 2.0938(1.5191-2.6684) 0.5(0.177-0.823) AC007608.44.99e-06 Up 77.8125(55.1936-100.4314) 17.4107(7.2275-27.5939) AC103702.2 5.09e-06 Up 190.3281(157.8536-222.8027) 89.8929(63.2628-116.5229) DLX6-AS1 5.34e-06 Up 5.2188(3.6374-6.8001) 1.1071(0.5301-1.6842) MSLN 5.54e-06 Up 22.4688(14.774-30.1635) 3.2143(2.0568-4.3718) AC004264.1 5.84e-06 Up 3.0156(2.4328-3.5985) 1.3393(0.9461-1.7325) HES5 6.29e-06 Up 8.2188(6.4277-10.0098) 3.3929(2.4698-4.3159)

[0942] GGH 6.68e-06 Up 231.1875(192.1638-270.2112) 117.1607(88.7982-145.5232) SLC28A3 6.75e-06 Up 17.6719(13.2188-22.125) 5.8393(3.6806-7.9979) AC002057.26.88e-06 Up 1.6094(1.1904-2.0283) 0.4464(0.1915-0.7014) AP001042.1 6.91e-06 Up 6.7656(5.5749-7.9563) 3.1607(2.1988-4.1226) AP001830.1 6.92e-06 Up 4.25(3.5959-4.9041) 2.0714(1.4157-2.7271)

[0943] CPNE7 7.81e-06 Up 7.2031(5.7129-8.6934) 2.8036(1.66-3.9471)

[0944] CARMIL3 8.17e-06 Up 3.5312(2.7669-4.2956) 1.375(0.8629-1.8871) SLC22A11 8.66e-06 Up 5.125(3.6526-6.5974) 1.1964(0.4079-1.985)

[0945] GRM8 8.71e-06 Up 7.9062(6.3241-9.4884) 3.1786(1.9038-4.4533) LINC00853 9.80e-06 Up 1.7344(1.4221-2.0467) 0.75(0.46-1.04)

[0946] TMEM211 1.06e-05 Up 3.5(2.6233-4.3767) 1.1071(0.5603-1.654)

[0947] TBX3 1.09e-05 Up 150.9844(125.337-176.6318) 71.0893(47.5889-94.5896) AP000619.1 1.26e-05 Up 1.3438(0.9353-1.7522) 0.3214(0.1591-0.4838) AC015660.1 1.27e-05 Up 4.9844(4.0882-5.8806) 2.4107(1.726-3.0954) NOX1 1.32e-05 Up 229.8594(187.746-271.9727) 112.1964(82.409-141.9839) AP003774.4 1.34e-05 Up 13.1562(10.571-15.7415) 5.8929(4.0265-7.7592) PROX1 1.38e-05 Up 72.2188(56.6264-87.8111) 30.4286(20.8436-40.0135) CRB2 1.41e-05 Up 1.8906(1.4752-2.306) 0.7321(0.4366-1.0277) AC069243.1 1.42e-05 Up 3.4062(2.6357-4.1768) 1.2857(0.7606-1.8108) GATA2-AS1 1.43e-05 Up 8.2656(5.9572-10.5741) 2.375(1.2532-3.4968) ASRGL1 1.46e-05 Up 41.0938(33.7022-48.4853) 20.1964(14.6786-25.7142) FGFRL1 1.54e-05 Up 61.3125(49.9922-72.6328) 29.8393(21.7424-37.9362) LINC02562 1.55e-05 Up 25.1406(20.2348-30.0464) 11.8929(8.7116-15.0741) SLCO4A1-AS1 1.56e-05 Up 4.4844(3.4321-5.5366) 1.6964(1.0629-2.33) AL133297.2 1.64e-05 Up 2.2188(1.5949-2.8426) 0.6607(0.3844-0.937) LINC01730 1.68e-05 Up 3.625(2.842-4.408) 1.625(1.2211-2.0289) AC005833.2 1.68e-05 Up 6.1719(5.1032-7.2405) 3.0357(2.1352-3.9363) AC021037.1 1.71e-05 Up 2.3438(1.8301-2.8574) 0.9821(0.6653-1.299) AC022182.1 1.93e-05 Up 1.8906(1.4705-2.3108) 0.75(0.46-1.04) LNCTAM34A 1.99e-05 Up 5.1562(4.3293-5.9832) 2.5536(1.7239-3.3832) AL158064.1 2.02e-05 Up 3.5312(2.7813-4.2812) 1.4643(0.9167-2.0118) XACT 2.08e-05 Up 5.8594(4.4077-7.311) 2.1429(1.3363-2.9494)

[0948] XKRX 2.41e-05 Up 3.5625(2.8126-4.3124) 1.3929(0.7516-2.0341) AC007608.1 2.63e-05 Up 11.4219(7.7567-15.0871) 2.6964(1.3396-4.0533) AC239800.2 2.73e-05 Up 5.75(3.9285-7.5715) 1.4286(0.763-2.0941) CERNA2 2.86e-05 Up 7.7656(6.2763-9.2549) 3.7679(2.7015-4.8342) CYP19A1 2.95e-05 Up 1.2656(0.9565-1.5748) 0.4643(0.2667-0.6618) LINC01301 3.02e-05 Up 5.0938(3.7294-6.4581) 1.8036(1.1963-2.4109) AC010809.1 3.42e-05 Up 0.6562(0.4465-0.866) 0.1429(0.0354-0.2503) AC005307.1 3.54e-05 Up 2.7812(1.7678-3.7947) 0.4643(0.1894-0.7391) CCDC33 3.62e-05 Up 1.2188(0.7771-1.6604) 0.1964(0.0482-0.3446)

[0949] C2orf15 3.73e-05 Up 6.3906(4.9969-7.7843) 3(2.2887-3.7113)

[0950] LINC02163 3.76e-05 Up 1.6094(1.0229-2.1958) 0.25(0.0441-0.4559)

[0951] ART3 3.77e-05 Up 16.2656(10.7391-21.7922) 3.7143(2.2956-5.1329) HOXB6 3.84e-05 Up 121.5938(98.2811-144.9064) 59.0357(41.458-76.6134) AP005271.1 3.91e-05 Up 1.3438(0.8744-1.8131) 0.25(0.0713-0.4287) GABRB1 3.91e-05 Up 8.625(6.6554-10.5946) 3.8393(2.8246-4.854)

[0952] SLC6A6 3.93e-05 Up 9.4219(7.5233-11.3205) 4.5179(3.2432-5.7925) LEFTY1 4.47e-05 Up 289.8594(231.3222-348.3965) 131.6429(85.4323-177.8534) AC009005.1 4.88e-05 Up 1.5938(1.2586-1.9289) 0.6786(0.4031-0.9541) C2CD4A 5.01e-05 Up 24.1562(16.4802-31.8323) 6.375(3.1864-9.5636) LINC01659 5.01e-05 Up 5.6719(4.0095-7.3342) 1.8929(1.3181-2.4676) LINC02254 5.15e-05 Up 5.8281(3.9089-7.7474) 1.2679(0.3077-2.228) AL590438.1 5.24e-05 Up 2.4375(1.866-3.009) 1(0.6282-1.3718)

[0953] NKD1 5.92e-05 Up 133.8906(91.2418-176.5394) 35.3929(16.5911-54.1946) CCDC60 5.95e-05 Up 4.5(3.2642-5.7358) 1.625(1.0505-2.1995) SCARNA226.11e-05 Up 16.1875(12.0377-20.3373) 6.375(4.2274-8.5226) ALDH1L1 6.29e-05 Up 11.9688(9.6733-14.2642) 6.0179(4.3069-7.7288) DUOX2 6.34e-05 Up 425.2188(269.6697-580.7678) 84.0179(45.1508-122.8849) LINC01555 6.61e-05 Up 1.3125(0.9596-1.6654) 0.4107(0.1565-0.6649) AC013470.2 7.28e-05 Up 6.3281(5.1388-7.5174) 2.6786(1.3615-3.9956) RCC2P6 7.57e-05 Up 1.5781(1.178-1.9782) 0.6071(0.3586-0.8556) VPS9D1-AS1 7.73e-05 Up 3.0625(2.4301-3.6949) 1.25(0.6303-1.8697) ARHGEF38-IT1 8.80e-05 Up 2.3438(1.7463-2.9412) 0.9286(0.579-1.2781) RASSF10 8.97e-05 Up 11.6094(8.8638-14.355) 4.9286(3.1333-6.7238) NPFFR1 9.18e-05 Up 3.0156(2.2987-3.7326) 1.3036(0.8645-1.7426) CCDC192 9.31e-05 Up 2.4688(1.946-2.9915) 1.1071(0.6839-1.5304) KCTD16 9.79e-05 Up 12.8594(8.068-17.6508) 2.4643(0.8543-4.0743) EDAR 1.06e-04 Up 6.7188(5.0514-8.3861) 2.8929(2-3.7857)

[0954] ITLN1 1.07e-04 Up 911.0781(669.235-1152.9213) 383.7143(292.0943-475.3342) LINC01411 1.15e-04 Up 3.1094(1.9334-4.2853) 0.6071(0.2545-0.9598) AL606537.1 1.15e-04 Up 4.3125(3.3006-5.3244) 1.75(0.9601-2.5399) SETD6P1 1.33e-04 Up 1.5938(1.1109-2.0766) 0.5179(0.2784-0.7573) CDH3 1.34e-04 Up 34.125(26.1246-42.1254) 13.6964(7.143-20.2498) DBNDD1 1.37e-04 Up 2.3125(1.7123-2.9127) 0.9643(0.6496-1.2789) SLCO1B3 1.46e-04 Up 17.6406(10.4779-24.8033) 2.8571(1.1973-4.517) FIRRE 1.50e-04 Up 5.4844(3.8078-7.1609) 1.9643(1.4215-2.5071)

[0955] IFI6 1.57e-04 Up 194.0781(136.1145-252.0418) 71.7679(51.0182-92.5175) C2CD4B 1.79e-04 Up 22.3281(16.3117-28.3446) 9.3036(6.4507-12.1565) DLX6 1.83e-04 Up 2.2344(1.4729-2.9959) 0.5893(0.229-0.9496) ZDHHC8P1 1.85e-04 Up 30.9219(22.9359-38.9078) 12.7679(7.8944-17.6413) AP006565.1 1.98e-04 Up 1.1875(0.8235-1.5515) 0.3929(0.204-0.5817) WDR72 2.13e-04 Up 15.5156(10.0435-20.9878) 4.4464(2.9576-5.9352) AC018629.1 2.39e-04 Up 7.6875(5.5582-9.8168) 3.1964(2.2162-4.1766) LINC019962.42e-04 Up 4.4219(2.8758-5.968) 1.2321(0.6258-1.8385) CCDC88B 2.45e-04 Up 113.6562(90.1115-137.201) 57.9286(40.2851-75.572) AC000099.1 2.49e-04 Up 1.3281(0.9583-1.698) 0.4821(0.232-0.7323) MSX1 2.54e-04 Up 32.6562(20.6545-44.658) 8.7143(5.4705-11.9581) AC078993.1 3.11e-04 Up 19.9844(11.8162-28.1526) 3.9107(1.625-6.1964) SPTBN2 3.17e-04 Up 5.1094(4.0866-6.1322) 2.375(1.3129-3.4371) CCDC195 3.37e-04 Up 0.875(0.5849-1.1651) 0.2679(0.119-0.4167) KIAA0319 3.62e-04 Up 5.1875(3.9892-6.3858) 2.5(1.6655-3.3345) CYP4A22-AS1 3.68e-04 Up 1.125(0.8215-1.4285) 0.4464(0.2364-0.6565) AL589669.1 3.75e-04 Up 6.375(4.5598-8.1902) 2.5536(1.553-3.5542) CUBNP3 3.76e-04 Up 0.8281(0.4876-1.1687) 0.1607(0.0491-0.2723) AC092185.1 4.19e-04 Up 0.8906(0.5398-1.2414) 0.1964(0.0573-0.3355) SALL4 4.22e-04 Up 7.2656(5.5464-8.9849) 3.5(2.3479-4.6521)

[0956] GAPLINC 4.30e-04 Up 2.8281(2.1687-3.4876) 1.25(0.6808-1.8192) AC013470.1 4.61e-04 Up 1.5781(1.1707-1.9856) 0.7143(0.4656-0.963) NPW 4.74e-04 Up 6.5469(4.6404-8.4534) 2.4643(1.2451-3.6835)

[0957] RNU1-30P 5.06e-04 Up 1.5312(1.121-1.9415) 0.6071(0.2937-0.9206) AC005833.1 5.19e-04 Up 14.4375(10.5494-18.3256) 6.0714(3.4766-8.6663) AL354743.2 5.21e-04 Up 1.1875(0.6687-1.7063) 0.1964(0.0239-0.369) SPINK4 5.22e-04 Up 896.875(671.3772-1122.3728) 389.4821(216.4551-562.5092) LINC02577 5.30e-04 Up 1.0625(0.5793-1.5457) 0.1607(0.0491-0.2723) RAD51AP2 5.32e-04 Up 2.1562(1.6144-2.6981) 1(0.6462-1.3538)

[0958] KCNV1 5.71e-04 Up 6.0312(4.5754-7.4871) 2.8214(1.7452-3.8976) SLC35D3 5.99e-04 Up 1.3906(0.9039-1.8774) 0.4643(0.2876-0.6409) LINC01357 6.28e-04 Up 2.1094(1.4401-2.7786) 0.75(0.3704-1.1296) CXCL3 6.82e-04 Up 166.4062(120.8105-212.002) 63.0357(25.1988-100.8727) NOTUM 7.04e-04 Up 22.2031(13.6729-30.7333) 5.4643(1.1816-9.747) AL023284.2 7.30e-04 Up 0.9844(0.6619-1.3068) 0.3571(0.2003-0.514) KLK12 7.61e-04 Up 6.9219(4.0922-9.7516) 1.7143(0.8272-2.6013) RHBDL3 8.15e-04 Up 1.2188(0.8425-1.595) 0.4643(0.2419-0.6867) AL445490.1 8.60e-04 Up 1.9375(1.1758-2.6992) 0.5(0.1651-0.8349) APCDD1 9.25e-04 Up 173.2031(115.7793-230.627) 65.4643(40.1012-90.8273) AC010378.2 9.33e-04 Up 1.3906(0.8025-1.9787) 0.3214(0.1229-0.5199) ETV4 9.60e-04 Up 18.7031(12.478-24.9283) 6.9286(3.9689-9.8882) APIP 9.78e-04 Up 104.3906(74.5459-134.2354) 46.3571(29.8066-62.9077) AC053545.1 0.001 Up 2.3281(1.6132-3.0431) 0.8571(0.3609-1.3534) MMP12 0.001 Up 78.0938(50.0165-106.171) 27.7143(18.8073-36.6213) PKD1L3 0.001 Up 1.0938(0.6088-1.5787) 0.2321(0.0971-0.3672) AC097504.2 0.001 Up 0.9219(0.5791-1.2646) 0.2857(0.135-0.4365) AC078883.3 0.001 Up 1.4688(1.0149-1.9226) 0.5536(0.2561-0.851) AC084375.1 0.001 Up 0.9062(0.612-1.2005) 0.2679(0.0257-0.51) LINC01132 0.001 Up 0.8906(0.6087-1.1725) 0.3214(0.1296-0.5132) LCN2 0.001 Up 1003.2344(514.4605-1492.0083) 161.3036(67.3015-255.3057) AP000344.1 0.001 Up 1.7188(1.1029-2.3346) 0.5714(0.2656-0.8772) AC007493.1 0.001 Up 2.7656(1.5808-3.9505) 0.5357(-0.0917~1.1632) AC109441.1 0.001 Up 2.0312(1.3136-2.7489) 0.5714(0.056-1.0868) AATBC 0.001 Up 4.7812(3.5056-6.0569) 2.2321(1.3595-3.1048) LINC02253 0.001 Up 2.8438(1.7071-3.9804) 0.6071(-0.1306-1.3449) RPL12P13 0.001 Up 1.1562(0.844-1.4685) 0.5357(0.3254-0.7461) MMP7 0.001 Up 39.3125(25.7144-52.9106) 12.4821(3.505-21.4593) SNORA79 0.001 Up 1.2188(0.7749-1.6626) 0.4107(0.2079-0.6136) LINC00923 0.001 Up 10.9062(8.6239-13.1886) 6.125(4.3-7.95) LY6G6F-LY6G6D 0.002 Up 17.9062(11.805-24.0075) 6.3571(2.7688-9.9455) SLC12A9-AS1 0.002 Up 1.4844(1.1041-1.8646) 0.6607(0.3248-0.9967) LINC01594 0.002 Up 2.5469(1.7684-3.3253) 1(0.4406-1.5594) AC093425.1 0.002 Up 3.3906(2.5949-4.1863) 1.6429(0.8881-2.3976) AC006206.1 0.002 Up 2.6406(1.6826-3.5987) 0.9643(0.5341-1.3945) TFAP2A-AS1 0.002 Up 1.0156(0.6666-1.3646) 0.3571(0.132-0.5822) ASCL5 0.002 Up 0.9062(0.577-1.2355) 0.3036(0.113-0.4941) AC097504.1 0.002 Up 2.25(1.6301-2.8699) 1.0714(0.657-1.4859) AC093817.2 0.002 Up 1.4688(0.7484-2.1891) 0.2679(0.0311-0.5046) CASC9 0.002 Up 21.8281(16.8059-26.8504) 11.5179(7.1915-15.8442) TMPRSS5 0.003 Up 5.0312(3.3821-6.6804) 2.3393(1.833-2.8455) AC004034.1 0.003 Up 1.1719(0.7368-1.6069) 0.4107(0.1779-0.6435) ATP5F1AP3 0.003 Up 1.0156(0.5585-1.4727) 0.25(0.0572-0.4428) LEMD1 0.003 Up 1(0.612-1.388) 0.2857(0.0121-0.5594)

[0959] REG1B 0.003 Up 225.3594(87.3134-363.4054) 12.8036(-3.3621-28.9692) DMRTA2 0.003 Up 2.3594(1.3248-3.394) 0.6071(0.0723-1.142)

[0960] SOX1 0.003 Up 1.9219(0.9284-2.9154) 0.3571(0.0754-0.6388) LINC02443 0.003 Up 1.6094(0.9696-2.2491) 0.5536(0.2651-0.8421) CHST4 0.004 Up 1.2969(0.6539-1.9398) 0.2857(0.0966-0.4748) C2orf70 0.004 Up 3.3594(2.5028-4.2159) 1.6964(0.978-2.4149) AC011700.1 0.004 Up 1.3438(0.7857-1.9018) 0.4286(0.1791-0.678) AC090116.1 0.004 Up 2.1875(1.5567-2.8183) 0.8929(0.285-1.5007) CYP4Z1 0.004 Up 1.9375(1.2775-2.5975) 0.7857(0.3749-1.1965) AC090498.1 0.004 Up 8.5156(5.9803-11.0509) 4.0536(2.375-5.7322) IGFL4 0.004 Up 1.2812(0.8626-1.6999) 0.5179(0.2073-0.8285) RAET1L 0.004 Up 2.3281(1.3419-3.3144) 0.6964(0.1758-1.217) LINC01833 0.005 Up 4.1562(2.479-5.8335) 1.5357(0.8719-2.1995) CCDC196 0.005 Up 5.4531(3.7066-7.1996) 2.5536(1.5634-3.5437)

[0961] BOK-AS1 0.005 Up 1.8281(0.7511-2.9051) 0.2321(0.0481-0.4162) LCN150.005 Up 24.7969(12.66-36.9337) 5.7857(0.7929-10.7785) CASC8 0.005 Up 2.8594(1.9716-3.7471) 1.1607(0.3749-1.9465)

[0962] REN 0.005 Up 2.6406(1.3497-3.9316) 0.6429(0.1414-1.1443)

[0963] SHISA60.005 Up 6.1406(3.7234-8.5579) 2.25(1.0114-3.4886) PROX1-AS1 0.005 Up 1.8125(1.1928-2.4322) 0.8036(0.4671-1.1401) MIR3142HG 0.006 Up 26.6875(18.8453-34.5297) 13.0179(7.3057-18.73) AC024236.1 0.006 Up 2.7656(1.8825-3.6488) 1.25(0.6367-1.8633) PLA2G2A 0.006 Up 707.5156(423.8853-991.146) 270.0536(141.5169-398.5903) AC074124.1 0.007 Up 1.0625(0.6931-1.4319) 0.4107(0.1139-0.7075) PRKCG 0.007 Up 1.6875(1.0306-2.3444) 0.7143(0.4656-0.963) AC024592.2 0.007 Up 1.4219(0.984-1.8598) 0.6429(0.2766-1.0091) ZNF736P9Y 0.007 Up 1.8438(0.977-2.7105) 0.5714(0.245-0.8979) AC090578.2 0.008 Up 1.2344(0.7393-1.7295) 0.4821(0.2427-0.7216) CDH70.008 Up 2.5(1.3241-3.6759) 0.7679(0.2998-1.2359)

[0964] LINC015490.008 Up 0.9219(0.3637-1.4801) 0.1429(0.0354-0.2503) AC010086.3 0.008 Up 8.0938(5.3398-10.8477) 3.7321(2.0683-5.396) CCL200.008 Up 115.7188(76.2413-155.1962) 52.9643(28.3929-77.5356) IGLV6-57 0.010 Up 4.3594(2.2797-6.439) 1.4107(0.602-2.2194) AL121761.1 0.010 Up 2.9844(1.3058-4.663) 0.7143(0.323-1.1056) UPK3A 0.011 Up 2.375(1.5634-3.1866) 1.0893(0.5246-1.654)

[0965] PI30.011 Up 82.4688(41.7717-123.1658) 26.875(14.6211-39.1289) AC005725.1 0.011 Up 3.5(1.8587-5.1413) 1.1786(0.4562-1.901)

[0966] EPHX40.012 Up 6.7344(4.1846-9.2842) 2.9286(1.4233-4.4339) AL669983.1 0.012 Up 87.2188(51.4563-122.9812) 38.3571(25.8871-50.8271) AL359075.1 0.014 Up 0.9062(0.4275-1.385) 0.2679(0.1024-0.4333) TRIM540.015 Up 2.7344(1.5659-3.9028) 1.1071(0.5079-1.7064) AC144450.1 0.015 Up 0.8594(0.5121-1.2066) 0.3571(0.1439-0.5703) TMPRSS13 0.015 Up 4.8125(3.6209-6.0041) 2.3214(0.6856-3.9573) KLK100.016 Up 8.1719(5.4281-10.9156) 4.0893(2.1845-5.9941)

[0967] REG1A 0.017 Up 1437.125(745.5756-2128.6744) 484.5357(112.8535-856.218) AC005702.2 0.017 Up 8.5469(4.8838-12.2099) 3.9821(3.2136-4.7507) QPCT 0.017 Up 56.5938(42.0408-71.1467) 29.9464(13.2958-46.5971) SLC5A80.018 Up 3.0781(1.7032-4.453) 1.3214(0.8587-1.7842) AC104964.1 0.018 Up 2(1.0966-2.9034) 0.8036(0.3969-1.2103)

[0968] GRPR 0.018 Up 1.7969(0.6421-2.9516) 0.3571(0.0801-0.6342)

[0969] TBX180.019 Up 4.5(2.3333-6.6667) 1.7143(0.8633-2.5653)

[0970] LINC02413 0.020 Up 1.0781(0.6945-1.4618) 0.5357(0.2857-0.7857) AL022068.1 0.020 Up 3.1562(2.2907-4.0218) 1.7143(0.8496-2.579) MTATP8P2 0.021 Up 30.5625(14.9724-46.1526) 10.0714(2.2838-17.859) AL359636.2 0.021 Up 3.9375(2.4165-5.4585) 1.875(0.983-2.767) RPS2P46 0.024 Up 364.4375(191.4318-537.4432) 148.1429(74.3684-221.9173) BEST30.024 Up 2(0.9365-3.0635) 0.5893(-0.0336~1.2122)

[0971] S0X140.026 Up 1.6094(0.8326-2.3862) 0.4821(-0.1454~l.1097)

[0972] CABP70.027 Up 1.7344(0.603-2.8658) 0.4286(0.1898-0.6673)

[0973] NPSR1-AS1 0.028 Up 2.6094(1.5416-3.6772) 0.9821(-0.0257~1.99) IGHGP 0.030 Up 140.1406(78.5612-201.7201) 61.1607(24.0905-98.2309) HSPA40.033 Up 1170.4219(203.6229-2137.2209) 116.8571(69.5923-164.122) AC036176.3 0.038 Up 3.5938(1.9484-5.2391) 1.6429(0.7801-2.5056) TCN1 0.045 Up 24.4531(13.1729-35.7333) 9.3214(-0.4532~19.0961) RPL17P360.049 Up 12.9844(7.3706-18.5981) 6.4821(3.1287-9.8355) PLA2G4D 0.052 Up 5.5625(4.2827-6.8423) 2.625(-0.0654~5.3154) TNFSF90.061 Up 6.2656(1.4777-11.0536) 1.6429(0.9475-2.3383)

[0974] IGHG2 0.061 Up 33.4688(5.5982-61.3393) 6.6607(3.5014-9.82)

[0975] IGLV3-10 0.064 Up 2.75(0.867-4.633) 0.9286(0.4694-1.3878)

[0976] RN7SL3 0.069 Up 2.0938(0.8923-3.2952) 0.9107(0.4647-1.3567) SN0RD3A 0.069 Up 35(16.8462-53.1538) 15.25(3.7409-26.7591) CXCL1 0.076 Up 202.8125(65.4435-340.1815) 71.6429(22.9354-120.3504) LINC024320.077 Up 5.7344(3.8597-7.6091) 3.0893(0.7871-5.3915) AL161431.1 0.100 Up 3.0625(2.2542-3.8708) 1.5893(0.0105-3.1681) DHRS40.113 Up 22.0625(10.1967-33.9283) 11.4286(5.441-17.4161) KLK60.130 Up 5.4375(2.8762-7.9988) 2.6071(-0.079~5.2933)

[0977] FEZF1 0.145 Up 1.3281(-0.0394~2.6956) 0.3036(0.0538-0.5533)

[0978] PURPL 0.158 Up 2.7344(0.8809-4.5878) 1.3393(0.7091-1.9695) TBC1D3E 0.167 Up 9.7031(1.2173-18.1889) 3.7321(2.7558-4.7084)

[0979]

[0980] Table 51: List C3-1 of t-test Results for comparison between LG. AP vs healthy (only with ncRNA without protein coding)

[0981]

[0982] GAU1 3.50e-06 Up 25.3594(21.1281-29.5906) 12.0714(8.6313-15.5115) AC007608.23.77e-06 Up 1.6875(1.0873-2.2877) 0.1429(0.0134-0.2723) AC078883.24.62e-06 Up 66.4219(56.7704-76.0733) 33.8571(24.3267-43.3876) AC007608.44.99e-06 Up 77.8125(55.1936-100.4314) 17.4107(7.2275-27.5939) AC103702.25.09e-06 Up 190.3281(157.8536-222.8027) 89.8929(63.2628-116.5229) DLX6-AS1 5.34e-06 Up 5.2188(3.6374-6.8001) 1.1071(0.5301-1.6842) AC004264.1 5.84e-06 Up 3.0156(2.4328-3.5985) 1.3393(0.9461-1.7325) AC002057.26.88e-06 Up 1.6094(1.1904-2.0283) 0.4464(0.1915-0.7014) AP001042.1 6.91e-06 Up 6.7656(5.5749-7.9563) 3.1607(2.1988-4.1226) AP001830.1 6.92e-06 Up 4.25(3.5959-4.9041) 2.0714(1.4157-2.7271) LINC00853 9.80e-06 Up 1.7344(1.4221-2.0467) 0.75(0.46-1.04)

[0983] AP000619.1 1.26e-05 Up 1.3438(0.9353-1.7522) 0.3214(0.1591-0.4838) AC015660.1 1.27e-05 Up 4.9844(4.0882-5.8806) 2.4107(1.726-3.0954) AP003774.4 1.34e-05 Up 13.1562(10.571-15.7415) 5.8929(4.0265-7.7592) AC069243.1 1.42e-05 Up 3.4062(2.6357-4.1768) 1.2857(0.7606-1.8108) GATA2-AS1 1.43e-05 Up 8.2656(5.9572-10.5741) 2.375(1.2532-3.4968) LINC02562 1.55e-05 Up 25.1406(20.2348-30.0464) 11.8929(8.7116-15.0741) SLCO4A1-AS1 1.56e-05 Up 4.4844(3.4321-5.5366) 1.6964(1.0629-2.33) AL133297.2 1.64e-05 Up 2.2188(1.5949-2.8426) 0.6607(0.3844-0.937) LINC01730 1.68e-05 Up 3.625(2.842-4.408) 1.625(1.2211-2.0289) AC005833.2 1.68e-05 Up 6.1719(5.1032-7.2405) 3.0357(2.1352-3.9363) AC021037.1 1.71e-05 Up 2.3438(1.8301-2.8574) 0.9821(0.6653-1.299) AC022182.1 1.93e-05 Up 1.8906(1.4705-2.3108) 0.75(0.46-1.04) LNCTAM34A 1.99e-05 Up 5.1562(4.3293-5.9832) 2.5536(1.7239-3.3832) AL158064.1 2.02e-05 Up 3.5312(2.7813-4.2812) 1.4643(0.9167-2.0118) XACT 2.08e-05 Up 5.8594(4.4077-7.311) 2.1429(1.3363-2.9494) AC007608.1 2.63e-05 Up 11.4219(7.7567-15.0871) 2.6964(1.3396-4.0533) AC239800.2 2.73e-05 Up 5.75(3.9285-7.5715) 1.4286(0.763-2.0941) CERNA2 2.86e-05 Up 7.7656(6.2763-9.2549) 3.7679(2.7015-4.8342) LINC01301 3.02e-05 Up 5.0938(3.7294-6.4581) 1.8036(1.1963-2.4109) AC010809.1 3.42e-05 Up 0.6562(0.4465-0.866) 0.1429(0.0354-0.2503) AC005307.1 3.54e-05 Up 2.7812(1.7678-3.7947) 0.4643(0.1894-0.7391) LINC02163 3.76e-05 Up 1.6094(1.0229-2.1958) 0.25(0.0441-0.4559) AP005271.1 3.91e-05 Up 1.3438(0.8744-1.8131) 0.25(0.0713-0.4287) AC009005.1 4.88e-05 Up 1.5938(1.2586-1.9289) 0.6786(0.4031-0.9541) LINC01659 5.01e-05 Up 5.6719(4.0095-7.3342) 1.8929(1.3181-2.4676) LINC02254 5.15e-05 Up 5.8281(3.9089-7.7474) 1.2679(0.3077-2.228) AL590438.1 5.24e-05 Up 2.4375(1.866-3.009) 1(0.6282-1.3718)

[0984] SCARNA22 6.11e-05 Up 16.1875(12.0377-20.3373) 6.375(4.2274-8.5226) RCC2P6 7.57e-05 Up 1.5781(1.178-1.9782) 0.6071(0.3586-0.8556)

[0985] VPS9D1-AS1 7.73e-05 Up 3.0625(2.4301-3.6949) 1.25(0.6303-1.8697) ARHGEF38-IT1 8.80e-05 Up 2.3438(1.7463-2.9412) 0.9286(0.579-1.2781) LINC01411 1.15e-04 Up 3.1094(1.9334-4.2853) 0.6071(0.2545-0.9598) AL606537.1 1.15e-04 Up 4.3125(3.3006-5.3244) 1.75(0.9601-2.5399) SETD6P1 1.33e-04 Up 1.5938(1.1109-2.0766) 0.5179(0.2784-0.7573)

[0986] FIRRE 1.50e-04 Up 5.4844(3.8078-7.1609) 1.9643(1.4215-2.5071) ZDHHC8P1 1.85e-04 Up 30.9219(22.9359-38.9078) 12.7679(7.8944-17.6413) AP006565.1 1.98e-04 Up 1.1875(0.8235-1.5515) 0.3929(0.204-0.5817) AC018629.1 2.39e-04 Up 7.6875(5.5582-9.8168) 3.1964(2.2162-4.1766) LINC019962.42e-04 Up 4.4219(2.8758-5.968) 1.2321(0.6258-1.8385) AC000099.1 2.49e-04 Up 1.3281(0.9583-1.698) 0.4821(0.232-0.7323) AC078993.1 3.11e-04 Up 19.9844(11.8162-28.1526) 3.9107(1.625-6.1964) CYP4A22-AS1 3.68e-04 Up 1.125(0.8215-1.4285) 0.4464(0.2364-0.6565) AL589669.1 3.75e-04 Up 6.375(4.5598-8.1902) 2.5536(1.553-3.5542) CUBNP3 3.76e-04 Up 0.8281(0.4876-1.1687) 0.1607(0.0491-0.2723) AC092185.1 4.19e-04 Up 0.8906(0.5398-1.2414) 0.1964(0.0573-0.3355) GAPLINC 4.30e-04 Up 2.8281(2.1687-3.4876) 1.25(0.6808-1.8192) AC013470.1 4.61e-04 Up 1.5781(1.1707-1.9856) 0.7143(0.4656-0.963) RNU1-30P 5.06e-04 Up 1.5312(1.121-1.9415) 0.6071(0.2937-0.9206) AL354743.25.21e-04 Up 1.1875(0.6687-1.7063) 0.1964(0.0239-0.369) LINC02577 5.30e-04 Up 1.0625(0.5793-1.5457) 0.1607(0.0491-0.2723) LINC01357 6.28e-04 Up 2.1094(1.4401-2.7786) 0.75(0.3704-1.1296) AL023284.2 7.30e-04 Up 0.9844(0.6619-1.3068) 0.3571(0.2003-0.514) AL445490.1 8.60e-04 Up 1.9375(1.1758-2.6992) 0.5(0.1651-0.8349) AC010378.2 9.33e-04 Up 1.3906(0.8025-1.9787) 0.3214(0.1229-0.5199) AC053545.1 0.001 Up 2.3281(1.6132-3.0431) 0.8571(0.3609-1.3534) AC097504.2 0.001 Up 0.9219(0.5791-1.2646) 0.2857(0.135-0.4365) AC078883.3 0.001 Up 1.4688(1.0149-1.9226) 0.5536(0.2561-0.851) AC084375.1 0.001 Up 0.9062(0.612-1.2005) 0.2679(0.0257-0.51) LINC01132 0.001 Up 0.8906(0.6087-1.1725) 0.3214(0.1296-0.5132) AP000344.1 0.001 Up 1.7188(1.1029-2.3346) 0.5714(0.2656-0.8772) AC007493.1 0.001 Up 2.7656(1.5808-3.9505) 0.5357(-0.0917~1.1632) AC109441.1 0.001 Up 2.0312(1.3136-2.7489) 0.5714(0.056-1.0868) AATBC 0.001 Up 4.7812(3.5056-6.0569) 2.2321(1.3595-3.1048) LINC02253 0.001 Up 2.8438(1.7071-3.9804) 0.6071 (-0.1306-1.3449) RPL12P13 0.001 Up 1.1562(0.844-1.4685) 0.5357(0.3254-0.7461) SNORA79 0.001 Up 1.2188(0.7749-1.6626) 0.4107(0.2079-0.6136) SLC12A9-AS1 0.002 Up 1.4844(1.1041-1.8646) 0.6607(0.3248-0.9967) LINC01594 0.002 Up 2.5469(1.7684-3.3253) 1(0.4406-1.5594) AC093425.1 0.002 Up 3.3906(2.5949-4.1863) 1.6429(0.8881-2.3976) AC006206.1 0.002 Up 2.6406(1.6826-3.5987) 0.9643(0.5341-1.3945) TFAP2A-AS1 0.002 Up 1.0156(0.6666-1.3646) 0.3571(0.132-0.5822) AC097504.1 0.002 Up 2.25(1.6301-2.8699) 1.0714(0.657-1.4859) AC093817.2 0.002 Up 1.4688(0.7484-2.1891) 0.2679(0.0311-0.5046) CASC9 0.002 Up 21.8281(16.8059-26.8504) 11.5179(7.1915-15.8442) AC004034.1 0.003 Up 1.1719(0.7368-1.6069) 0.4107(0.1779-0.6435) ATP5F1AP3 0.003 Up 1.0156(0.5585-1.4727) 0.25(0.0572-0.4428) LINC02443 0.003 Up 1.6094(0.9696-2.2491) 0.5536(0.2651-0.8421) AC011700.1 0.004 Up 1.3438(0.7857-1.9018) 0.4286(0.1791-0.678) AC090116.1 0.004 Up 2.1875(1.5567-2.8183) 0.8929(0.285-1.5007) AC090498.1 0.004 Up 8.5156(5.9803-11.0509) 4.0536(2.375-5.7322) LINC01833 0.005 Up 4.1562(2.479-5.8335) 1.5357(0.8719-2.1995)

[0987] BOK-AS1 0.005 Up 1.8281(0.7511-2.9051) 0.2321(0.0481-0.4162) CASC8 0.005 Up 2.8594(1.9716-3.7471) 1.1607(0.3749-1.9465) PROX1-AS1 0.005 Up 1.8125(1.1928-2.4322) 0.8036(0.4671-1.1401) MIR3142HG 0.006 Up 26.6875(18.8453-34.5297) 13.0179(7.3057-18.73) AC024236.1 0.006 Up 2.7656(1.8825-3.6488) 1.25(0.6367-1.8633) AC024592.2 0.007 Up 1.4219(0.984-1.8598) 0.6429(0.2766-1.0091) ZNF736P9Y 0.007 Up 1.8438(0.977-2.7105) 0.5714(0.245-0.8979) AC090578.2 0.008 Up 1.2344(0.7393-1.7295) 0.4821(0.2427-0.7216) AC010086.3 0.008 Up 8.0938(5.3398-10.8477) 3.7321(2.0683-5.396) IGLV6-57 0.010 Up 4.3594(2.2797-6.439) 1.4107(0.602-2.2194) AC005725.1 0.011 Up 3.5(1.8587-5.1413) 1.1786(0.4562-1.901) AL669983.1 0.012 Up 87.2188(51.4563-122.9812) 38.3571(25.8871-50.8271) AL359075.1 0.014 Up 0.9062(0.4275-1.385) 0.2679(0.1024-0.4333) AC144450.1 0.015 Up 0.8594(0.5121-1.2066) 0.3571(0.1439-0.5703) AC005702.2 0.017 Up 8.5469(4.8838-12.2099) 3.9821(3.2136-4.7507) AC104964.1 0.018 Up 2(1.0966-2.9034) 0.8036(0.3969-1.2103) LINC02413 0.020 Up 1.0781(0.6945-1.4618) 0.5357(0.2857-0.7857) AL022068.1 0.020 Up 3.1562(2.2907-4.0218) 1.7143(0.8496-2.579) MTATP8P2 0.021 Up 30.5625(14.9724-46.1526) 10.0714(2.2838-17.859) AL359636.2 0.021 Up 3.9375(2.4165-5.4585) 1.875(0.983-2.767) RPS2P46 0.024 Up 364.4375(191.4318-537.4432) 148.1429(74.3684-221.9173) NPSR1-AS1 0.028 Up 2.6094(1.5416-3.6772) 0.9821(-0.0257~1.99) IGHGP 0.030 Up 140.1406(78.5612-201.7201) 61.1607(24.0905-98.2309) AC036176.3 0.038 Up 3.5938(1.9484-5.2391) 1.6429(0.7801-2.5056) RPL17P360.049 Up 12.9844(7.3706-18.5981) 6.4821(3.1287-9.8355) IGHG2 0.061 Up 33.4688(5.5982-61.3393) 6.6607(3.5014-9.82)

[0988] IGLV3-10 0.064 Up 2.75(0.867-4.633) 0.9286(0.4694-1.3878)

[0989] RN7SL3 0.069 Up 2.0938(0.8923-3.2952) 0.9107(0.4647-1.3567)

[0990]

[0991] Table 52: List C3-2 of t-test Results for comparison between LG. AP vs healthy (only with protein coding)

[0992]

[0993] ENC1 1.29e-07 Up 223.7188(193.1711-254.2664) 103.0536(72.8579-133.2493) HES6 1.29e-07 Up 119.875(102.7502-136.9998) 56.7857(42.2802-71.2913) MET 1.79e-07 Up 124.3438(102.4997-146.1878) 52.875(39.7235-66.0265) BACE2 1.97e-07 Up 281.3281(234.5993-328.057) 125.5357(94.6866-156.3848) CLCA1 2.01e-07 Up 4111.2656(3236.4063-4986.1249) 1392.3929(989.2431-1795.5426) OLFM4 2.19e-07 Up 5163.4375(3722.5127-6604.3623) 902.4286(550.5311-1254.326) TEX45 2.51e-07 Up 5.4844(4.3375-6.6312) 1.7857(1.0973-2.4741)

[0994] OXGR1 2.64e-07 Up 10.4375(8.2078-12.6672) 3.5536(2.4886-4.6186)

[0995] HOXA9 3.09e-07 Up 164.0625(138.9488-189.1762) 77.5(57.9288-97.0712) CLDN2 3.89e-07 Up 67.8438(52.9687-82.7188) 19.0893(8.8728-29.3058) GRIN2B 4.15e-07 Up 33.2969(24.566-42.0277) 6.75(2.4642-11.0358)

[0996] CCNO 5.31e-07 Up 18.5156(15.559-21.4722) 8.625(6.3673-10.8827)

[0997] AGT 6.19e-07 Up 29.4688(23.9555-34.982) 12.625(9.5522-15.6978)

[0998] SAMD5 6.86e-07 Up 118.7656(98.7581-138.7731) 51.3571(35.2883-67.426) LRRC36 8.18e-07 Up 5.5312(4.2899-6.7726) 1.8393(1.1999-2.4787)

[0999] MYB 8.23e-07 Up 168.5625(145.5008-191.6242) 86.2857(64.6553-107.9161) NANOS3 8.25e-07 Up 1.5156(1.1459-1.8853) 0.4107(0.2144-0.607)

[1000] C17orf77 8.85e-07 Up 6.6562(4.8472-8.4653) 1.1964(0.1694-2.2234)

[1001] FZD9 9.13e-07 Up 3.1094(2.2191-3.9996) 0.6429(0.4297-0.8561)

[1002] PF4 1.12e-06 Up 11.3594(8.199-14.5198) 2.4821(1.3334-3.6309)

[1003] LINC01124 1.25e-06 Up 2.3594(1.8396-2.8791) 0.8214(0.5321-1.1108)

[1004] CELSR3 1.49e-06 Up 9.5(8.0661-10.9339) 4.5893(3.2855-5.893)

[1005] SOX9 1.57e-06 Up 322.6875(263.6852-381.6898) 142.9107(103.9979-181.8236) FDXR 1.63e-06 Up 17.7188(14.756-20.6815) 8.6964(6.7332-10.6597)

[1006] TTPA 1.72e-06 Up 20.0625(16.6581-23.4669) 9.75(7.518-11.982)

[1007] SERPINA1 1.91e-06 Up 529.8906(391.8701-667.9112) 154.1786(107.5009-200.8563) GALNT8 2.00e-06 Up 13.6406(11.193-16.0882) 5.7857(3.8226-7.7488)

[1008] IQANK1 2.07e-06 Up 23.3906(19.4241-27.3571) 11.0179(8.0667-13.969)

[1009] KSR2 2.12e-06 Up 7.9688(6.5884-9.3491) 3.6964(2.6906-4.7022)

[1010] SP5 2.30e-06 Up 13.4688(10.306-16.6315) 4.4464(2.7574-6.1355)

[1011] SEMA3F 2.64e-06 Up 19.5938(16.3749-22.8126) 10.0893(8.0198-12.1588)

[1012] MB 3.53e-06 Up 16.0781(13.4962-18.66) 8.1071(6.1001-10.1142)

[1013] EGF 3.98e-06 Up 11.0781(8.8301-13.3262) 4.6071(3.1913-6.023)

[1014] ADAM32 4.03e-06 Up 6.5(5.3785-7.6215) 2.9464(1.9973-3.8955)

[1015] PCSK1 4.15e-06 Up 60.5781(40.8512-80.305) 10.5714(8.1578-12.9851) PDZK1IP1 4.22e-06 Up 133.4219(102.4217-164.422) 49.5179(35.0716-63.9641) TDGF1 4.27e-06 Up 19.9688(15.5888-24.3487) 7.2143(4.2951-10.1335)

[1016] ATOH8 4.90e-06 Up 29.5312(23.6838-35.3787) 13.0536(9.5308-16.5763) AC027808.2 4.96e-06 Up 2.0938(1.5191-2.6684) 0.5(0.177-0.823)

[1017] MSLN 5.54e-06 Up 22.4688(14.774-30.1635) 3.2143(2.0568-4.3718)

[1018] HES5 6.29e-06 Up 8.2188(6.4277-10.0098) 3.3929(2.4698-4.3159)

[1019] GGH 6.68e-06 Up 231.1875(192.1638-270.2112) 117.1607(88.7982-145.5232) SLC28A3 6.75e-06 Up 17.6719(13.2188-22.125) 5.8393(3.6806-7.9979)

[1020] CPNE7 7.81e-06 Up 7.2031(5.7129-8.6934) 2.8036(1.66-3.9471)

[1021] CARMIL3 8.17e-06 Up 3.5312(2.7669-4.2956) 1.375(0.8629-1.8871)

[1022] SLC22A11 8.66e-06 Up 5.125(3.6526-6.5974) 1.1964(0.4079-1.985)

[1023] GRM8 8.71e-06 Up 7.9062(6.3241-9.4884) 3.1786(1.9038-4.4533)

[1024] TMEM211 1.06e-05 Up 3.5(2.6233-4.3767) 1.1071(0.5603-1.654)

[1025] TBX3 1.09e-05 Up 150.9844(125.337-176.6318) 71.0893(47.5889-94.5896) NOX1 1.32e-05 Up 229.8594(187.746-271.9727) 112.1964(82.409-141.9839) PROX1 1.38e-05 Up 72.2188(56.6264-87.8111) 30.4286(20.8436-40.0135)

[1026] CRB2 1.41e-05 Up 1.8906(1.4752-2.306) 0.7321(0.4366-1.0277)

[1027] ASRGL1 1.46e-05 Up 41.0938(33.7022-48.4853) 20.1964(14.6786-25.7142) FGFRL1 1.54e-05 Up 61.3125(49.9922-72.6328) 29.8393(21.7424-37.9362) XKRX 2.41e-05 Up 3.5625(2.8126-4.3124) 1.3929(0.7516-2.0341)

[1028] CYP19A1 2.95e-05 Up 1.2656(0.9565-1.5748) 0.4643(0.2667-0.6618)

[1029] CCDC33 3.62e-05 Up 1.2188(0.7771-1.6604) 0.1964(0.0482-0.3446)

[1030] C2orf15 3.73e-05 Up 6.3906(4.9969-7.7843) 3(2.2887-3.7113)

[1031] ART3 3.77e-05 Up 16.2656(10.7391-21.7922) 3.7143(2.2956-5.1329)

[1032] HOXB6 3.84e-05 Up 121.5938(98.2811-144.9064) 59.0357(41.458-76.6134) GABRB1 3.91e-05 Up 8.625(6.6554-10.5946) 3.8393(2.8246-4.854) SLC6A6 3.93e-05 Up 9.4219(7.5233-11.3205) 4.5179(3.2432-5.7925) LEFTY1 4.47e-05 Up 289.8594(231.3222-348.3965) 131.6429(85.4323-177.8534) C2CD4A 5.01e-05 Up 24.1562(16.4802-31.8323) 6.375(3.1864-9.5636) NKD1 5.92e-05 Up 133.8906(91.2418-176.5394) 35.3929(16.5911-54.1946) CCDC60 5.95e-05 Up 4.5(3.2642-5.7358) 1.625(1.0505-2.1995)

[1033] ALDH1L1 6.29e-05 Up 11.9688(9.6733-14.2642) 6.0179(4.3069-7.7288) DUOX2 6.34e-05 Up 425.2188(269.6697-580.7678) 84.0179(45.1508-122.8849) LINC01555 6.61e-05 Up 1.3125(0.9596-1.6654) 0.4107(0.1565-0.6649) AC013470.2 7.28e-05 Up 6.3281(5.1388-7.5174) 2.6786(1.3615-3.9956) RASSF10 8.97e-05 Up 11.6094(8.8638-14.355) 4.9286(3.1333-6.7238) NPFFR1 9.18e-05 Up 3.0156(2.2987-3.7326) 1.3036(0.8645-1.7426) CCDC192 9.31e-05 Up 2.4688(1.946-2.9915) 1.1071(0.6839-1.5304) KCTD16 9.79e-05 Up 12.8594(8.068-17.6508) 2.4643(0.8543-4.0743) EDAR 1.06e-04 Up 6.7188(5.0514-8.3861) 2.8929(2-3.7857)

[1034] ITLN1 1.07e-04 Up 911.0781(669.235-1152.9213) 383.7143(292.0943-475.3342) CDH3 1.34e-04 Up 34.125(26.1246-42.1254) 13.6964(7.143-20.2498) DBNDD1 1.37e-04 Up 2.3125(1.7123-2.9127) 0.9643(0.6496-1.2789) SLCO1B3 1.46e-04 Up 17.6406(10.4779-24.8033) 2.8571(1.1973-4.517) IFI6 1.57e-04 Up 194.0781(136.1145-252.0418) 71.7679(51.0182-92.5175) C2CD4B 1.79e-04 Up 22.3281(16.3117-28.3446) 9.3036(6.4507-12.1565) DLX6 1.83e-04 Up 2.2344(1.4729-2.9959) 0.5893(0.229-0.9496)

[1035] WDR72 2.13e-04 Up 15.5156(10.0435-20.9878) 4.4464(2.9576-5.9352) CCDC88B 2.45e-04 Up 113.6562(90.1115-137.201) 57.9286(40.2851-75.572) MSX1 2.54e-04 Up 32.6562(20.6545-44.658) 8.7143(5.4705-11.9581) SPTBN2 3.17e-04 Up 5.1094(4.0866-6.1322) 2.375(1.3129-3.4371) CCDC195 3.37e-04 Up 0.875(0.5849-1.1651) 0.2679(0.119-0.4167) KIAA0319 3.62e-04 Up 5.1875(3.9892-6.3858) 2.5(1.6655-3.3345)

[1036] SALL4 4.22e-04 Up 7.2656(5.5464-8.9849) 3.5(2.3479-4.6521)

[1037] NPW 4.74e-04 Up 6.5469(4.6404-8.4534) 2.4643(1.2451-3.6835) AC005833.1 5.19e-04 Up 14.4375(10.5494-18.3256) 6.0714(3.4766-8.6663) SPINK4 5.22e-04 Up 896.875(671.3772-1122.3728) 389.4821(216.4551-562.5092) RAD51AP2 5.32e-04 Up 2.1562(1.6144-2.6981) 1(0.6462-1.3538)

[1038] KCNV1 5.71e-04 Up 6.0312(4.5754-7.4871) 2.8214(1.7452-3.8976) SLC35D3 5.99e-04 Up 1.3906(0.9039-1.8774) 0.4643(0.2876-0.6409) CXCL3 6.82e-04 Up 166.4062(120.8105-212.002) 63.0357(25.1988-100.8727) NOTUM 7.04e-04 Up 22.2031(13.6729-30.7333) 5.4643(1.1816-9.747) KLK12 7.61e-04 Up 6.9219(4.0922-9.7516) 1.7143(0.8272-2.6013) RHBDL3 8.15e-04 Up 1.2188(0.8425-1.595) 0.4643(0.2419-0.6867) APCDD1 9.25e-04 Up 173.2031(115.7793-230.627) 65.4643(40.1012-90.8273) ETV4 9.60e-04 Up 18.7031(12.478-24.9283) 6.9286(3.9689-9.8882)

[1039] APIP 9.78e-04 Up 104.3906(74.5459-134.2354) 46.3571(29.8066-62.9077) MMP12 0.001 Up 78.0938(50.0165-106.171) 27.7143(18.8073-36.6213) PKD1L3 0.001 Up 1.0938(0.6088-1.5787) 0.2321(0.0971-0.3672)

[1040] LCN2 0.001 Up 1003.2344(514.4605-1492.0083) 161.3036(67.3015-255.3057) MMP7 0.001 Up 39.3125(25.7144-52.9106) 12.4821(3.505-21.4593) LINC00923 0.001 Up 10.9062(8.6239-13.1886) 6.125(4.3-7.95)

[1041] LY6G6F-LY6G6D 0.002 Up 17.9062(11.805-24.0075) 6.3571(2.7688-9.9455) ASCL5 0.002 Up 0.9062(0.577-1.2355) 0.3036(0.113-0.4941)

[1042] TMPRSS5 0.003 Up 5.0312(3.3821-6.6804) 2.3393(1.833-2.8455)

[1043] LEMD1 0.003 Up 1(0.612-1.388) 0.2857(0.0121-0.5594)

[1044] REG1B 0.003 Up 225.3594(87.3134-363.4054) 12.8036(-3.3621-28.9692) DMRTA2 0.003 Up 2.3594(1.3248-3.394) 0.6071(0.0723-1.142)

[1045] SOX1 0.003 Up 1.9219(0.9284-2.9154) 0.3571(0.0754-0.6388)

[1046] CHST4 0.004 Up 1.2969(0.6539-1.9398) 0.2857(0.0966-0.4748)

[1047] C2orf70 0.004 Up 3.3594(2.5028-4.2159) 1.6964(0.978-2.4149)

[1048] CYP4Z1 0.004 Up 1.9375(1.2775-2.5975) 0.7857(0.3749-1.1965)

[1049] IGFL4 0.004 Up 1.2812(0.8626-1.6999) 0.5179(0.2073-0.8285)

[1050] RAET1L 0.004 Up 2.3281(1.3419-3.3144) 0.6964(0.1758-1.217)

[1051] CCDC196 0.005 Up 5.4531(3.7066-7.1996) 2.5536(1.5634-3.5437)

[1052]

[1053] Table 53: Al list

[1054]

[1055] Z80897.1, AC105020.2, RNU6-703P, TUBB4B, LYZ, RPS25, NOTCH2NLA, PHKA2-AS1, F8A1, LY6E, AP000224.1, RPL12P4, PXN, RNU6-194P, AC140847.2, AC012313.3, AC137932.3, RSKR, KRT18P13, RAD17P2, AL096870.10, AC067930.8, TOR2A, AC067817.2, LIF, AC078962.3, PDCD2L, WNT10B, AC104534.1, AL662844.3, SORD, LENG8, AC004830.1, AL157838.1, ZBTB16, HBB, AC002128.2, RPS7P10, AC007922.2, AL596247.1, RASGRP2, AC025181.1, AL591379.1, AL135978.2, AC020917.3, RPS28P7, TECRP1, AC092828.1, AC108449.2, AC004825.3, NBPF15, FCGR2C, OR7A19P, KLC2, AL157871.5, DAAM2, SMIM5, DEFA5, AC011476.3, PA2G4P6, AC011466.4, MST1L, CARNMT1-AS1, AC008750.5, MTOR-AS1, UCP3, UPF3AP2, RPS26P45, HIST1H4I, AC004765.1, AC087301.1, RNY1P11, AL445189.2, AC010323.2, SNHG6, FAM3D-AS1, C5orf17, MMP10, SNORD38C, AC114930.1, AC127024.4, AC103591.3, LINC01859, BMPR1B, CHIT1, FCF1P7, RNU6-437P, AC079174.1, AC093843.2, AC092338.3, AC092933.1, YWHAQP5, OAS2, RPL5P34, SLC25A25, EEF1B2P6, CDKN2A, MX1, AC023632.5, NDUFA4L2, AC124283.4, AC090617.4, FOXP1, AL137847.2, LRRIQ1, RNA5SP123, AC119396.2, GALNTL6, RPL18A, RBFOX3, SMG1P4, KLF16, RPL34P18, AC107982.2, AIRE, FTLP3, AC010998.2, CCDC89, RNU6-181P, AC068389.1, COX7CP1, CFP, MEA1, AC097658.1, PTH1R, RNU6-678P, AC118754.1, AC010999.2, ARRDC5, MRPL49, RPL27AP5, CELF3, AL035456.1, AL512506.2, H19, NOP56P1, RF00588, BTBD7P1, RN7SL784P, C8orf34, AC105137.2, RNU6-1064P, HLA-DRB6, AC100793.2, UBE2S, TBCAP1, AC104564.3, RN7SL388P, NMNAT2, AC022146.2, HIST1H2BL, KIR3DX1, RF00100, ARHGEF34P, AL157832.2, AC008802.1, AC104564.1, AC243967.3, AL135924.2, RNU6-1228P, DPYD-AS2, SEMA6A-AS2, THRB-IT1, RPL13AP6, AF129075.3, LINC00486, RNU7-119P, AF001548.3, RHD, HLA-G, GTF3C2-AS1, RNU5F-1, AC097382.2, FABP5, AC051619.4, AC020908.3, A2MP1, AL023284.3, SYT12, AL355388.3, PRDX2, RPS15AP16, AC011481.3, AL591163.1, MAMLD1, FZD10, LINC01531, ASGR2, UNC5B-AS1, AC023282.1, PRKCZ, LINC02664, AC010343.1, AL109659.2, VTRNA1-1, RFX6, RPL39P3, AC016747.3, UCN3, CLEC18A, AC022154.1, AL021393.1, OR5BA1P, PUSL1, DPPA4, AC010735.2, AC02074E1, EIF2S2P3, SPEG, AC005695.1, AC008429.1, PTCHD1, FUZ, NME2P1, AL033527.4, AC005828.4, AKT3-IT1, RAB6C, TRPC7-AS1, ARMH1, LINC02427, AC103858.1, PYY, AL022329.2, TPT1P9, AC107294.2, AC018445.4, EIF4BP3, AC135012.1, AC006115.2, AC113410.3, AC107075.1, AC093323.3, AC009303.2, AC040173.1, MRPS24, TLE5, ZNF334, PRDX1, PCDHA9, SNORD14A, AC008013.1, RNU6-570P, OPRM1, RPL30P4, MASI, THOC6, FTH1P7, UBQLN4, C16orf95, AC015920.1, AC145285.1, AC004466.1, FAM215B, IGLV3-10, CPS1, AC009159.4, MMP3, AP000350.6, EIF3FP3, AC02680E2, RN7SL801P, FBXO24, AL031729.1, CHGB, AL35494E1, ANKRD18B, PPIEL, ATP8A2, MROH3P, HSF1, MRPL53P1, LINC02316, AP003390.2, FABP5P7, Cllorf96, AC02627E1, C8orf31, LINC01203, C1QTNF9, NBEAP1, AC137936.1, AC233280.1, COX17P1, AL513190.1, UBE2V2P1, AP002340.1, KXD1, AC022535.1, AC009656.1, OR10AH1P, MIR1293, AC106872.3, TDRD1, AC107032.1, AC020779.1, VSTM2L, AC092979.1, AC002398.1, RNU6-1300P, IDO2, AC023302.1, AL022097.1, CR381670.1, EXOSC10-AS1, AC010884.2, RNU4-86P, PDZRN4, BOLA2B, AC012409.1, MALL, UGT2B15, SNRPEP2, TRMT112P6, LINC02293, PNP, CCDC81, AC139495.3, DSG3, AC139530.1, Z92544.2, AC091180.2, AC078785.2, AC116348.1, ZNF137P, LRAT, CD22, RPL23AP48, AL031651.2, AC106037.1, RPL35AP30, AC115618.1, SNRPFP1, FHAD1, RPLP1P10, ESMI, CYP4F2, RNU6-1216P, HNRNPCP2, FSD1, NOX4, AC089985.1, PFN1P1, VNN1, AP003035.1, AL139011.2, ARPC1B, AC005332.1, AC139887.4, RPL5P1, LINC01344, PRSS2, AL162734.1, SNORA80E, RPL7AP14, LLGL1, AC009974.1, AC091868.2, AL139118.1, ASB16, RPL7P1, SLC26A4-AS1, RNU6-892P, SMARCE1P5, AC004672.2, AP000879.2, REG3A, AC106820.2, ARL13A, FDPSP5, AC007160.1, RAMP2-AS1, COX6A1P2, RPS17, AC011453.1, TOMM20P4, AP001784.1, PLP2, FELL1, RNU6-90P, AC005392.2, TUBA3FP, LEXM, AL591845.2, ZNF726, AL355432.1, RNU1-73P, AC009063.3, AL590682.1, PSORS1C3, AC025262.2, AL391839.1, AC115837.1, DEFA6, AC006059.4, RPL39P38, WNT2, WDR17, RPL32P1, MORF4, TNNT1, AC022960.1, PIPOX, MIER2, AL138701.1, SNX32, ELOA2, U52111.1, AC007728.2, AC008945.2, AC012494.2, SHISA8, AL020995.1, RN7SL204P, SAG, CFAP99, TREM1, LINC00470, KIAA2012-AS1, SEMG1, CEACAM22P, HMGB1P21, KRT1, AC090666.1, AP003969.2, NR1I3, CNMD, SCNN1G, ASIC4, NUSAP1, IGLC3, CPB1, YBX1P6, IGHGP, PSMA6P1, CCR9, ODCP, AC092135.3, RN7SL211P, RNA5SP492, AC007387.3, AC122688.4, AC130456.4, AL590383.1, LINC00944, SLIT1, RNA5SP466, TPT1P4, AC005180.2, DHRS2, HLA-DQA2, AC110619.1, CSF3, AC074044.1, AC084125.2, FTH1P8, AC109322.2, AL592146.2, AC073842.2, PTMAP4, AC018553.2, PTP4A1P6, AC074029.1, RPS29P29, KRTAP5-9, AC126178.1, SNORD3B-1, DEFB109D, LINC02359, RNU6-204P, SNORD63, AC106028.2, YPEL4, EEF1A1P3, STAG3L3, AC093158.1, AC020604.1, FAM106A, PSCA, RDM1P3, RN7SL602P, EAF1-AS1, AC027763.1, RPS27P25, CCBE1, AC007458.1, SP100, IGKV4-1, AP3B2, PTPRVP, NOC2LP1, RPL35AP32,

[1056]

[1057] Table 54: Al- 1 list (only with ncRNA without protein coding)

[1058]

[1059]

[1060] Table 55: Markers in common between Al and B lists

[1061]

[1062] Table 56: A2 list

[1063]

[1064] RPL12P4, PXN, RNU6-194P, AC140847.2, AC012313.3, AC137932.3, RSKR, KRT18P13, RAD17P2, AL096870.10, AC067930.8, TOR2A, AC067817.2, LIF, AC078962.3, PDCD2L, WNT10B, AC104534.1, AL662844.3, SORD, LENG8, AC004830.1, AL157838.1, ZBTB16, HBB, AC002128.2, RPS7P10, AC007922.2, AL596247.1, RASGRP2, AC025181.1, AL591379.1, AL135978.2, AC020917.3, RPS28P7, TECRP1, AC092828.1, AC108449.2, AC004825.3, NBPF15, FCGR2C, OR7A19P, KLC2, AL157871.5, DAAM2, SMIM5, DEFA5, AC011476.3, PA2G4P6, AC011466.4, MST1L, CARNMT1-AS1, AC008750.5, MTOR-AS1, UCP3, UPF3AP2, RPS26P45, HIST1H4I, AC004765.1, AC087301.1, RNY1P11, AL445189.2, AC010323.2, SNHG6, FAM3D-AS1, C5orf17, MMP10, SNORD38C, AC114930.1, AC127024.4, AC103591.3, LINC01859, BMPR1B, CHIT1, FCF1P7, RNU6-437P, AC079174.1, AC093843.2, AC092338.3, AC092933.1, YWHAQP5, OAS2, RPL5P34, SLC25A25, EEF1B2P6, CDKN2A, MX1, AC023632.5, NDUFA4L2, AC124283.4, AC090617.4, FOXP1, AL137847.2, LRRIQ1, RNA5SP123, AC119396.2, GALNTL6, RPL18A, RBFOX3, SMG1P4, KLF16, RPL34P18, AC107982.2, AIRE, FTLP3, AC010998.2, CCDC89, RNU6-181P, AC068389.1, COX7CP1, CFP, MEA1, AC097658.1, PTH1R, RNU6-678P, AC118754.1, AC010999.2, ARRDC5, MRPL49, RPL27AP5, CELF3, AL035456.1, AL512506.2, H19, NOP56P1, RF00588, BTBD7P1, RN7SL784P, C8orf34, AC105137.2, RNU6-1064P, HLA-DRB6, AC100793.2, UBE2S, TBCAP1, AC104564.3, RN7SL388P, NMNAT2, AC022146.2, HIST1H2BL, KIR3DX1, RF00100, ARHGEF34P, AL157832.2, AC008802.1, AC104564.1, AC243967.3, AL135924.2, RNU6-1228P, DPYD-AS2, SEMA6A-AS2, THRB-IT1, RPL13AP6, AF129075.3, LINC00486, RNU7-119P, AF001548.3, RHD, HLA-G, GTF3C2-AS1, RNU5F-1, AC097382.2, FABP5, AC051619.4, AC020908.3, A2MP1, AL023284.3, SYT12, AL355388.3, PRDX2, RPS15AP16, AC011481.3, AL591163.1, MAMLD1, FZD10, LINC01531, ASGR2, UNC5B-AS1, AC023282.1, PRKCZ, LINC02664, AC010343.1, AL109659.2, VTRNA1-1, RFX6, RPL39P3, AC016747.3, UCN3, CLEC18A, AC022154.1, AL021393.1, OR5BA1P, PUSL1, DPPA4, AC010735.2, AC02074E1, EIF2S2P3, SPEG, AC005695.1, AC008429.1, PTCHD1, FUZ, NME2P1, AL033527.4, AC005828.4, AKT3-IT1, RAB6C, TRPC7-AS1, ARMH1, LINC02427, AC103858.1, PYY, AL022329.2, TPT1P9, AC107294.2, AC018445.4, EIF4BP3, AC135012.1, AC006115.2, AC113410.3, AC107075.1, AC093323.3, AC009303.2, AC040173.1, MRPS24, TLE5, ZNF334, PRDX1, PCDHA9, SNORD14A, AC008013.1, RNU6-570P, OPRM1, RPL30P4, MASI, THOC6, FTH1P7, UBQLN4, C16orf95, AC015920.1, AC145285.1, AC004466.1, FAM215B, IGLV3-10, CPS1, AC009159.4, MMP3, AP000350.6, EIF3FP3, AC02680E2, RN7SL801P, FBXO24, AL031729.1, CHGB, AL35494E1, ANKRD18B, PPIEL, ATP8A2, MROH3P, HSF1, MRPL53P1, LINC02316, AP003390.2, FABP5P7, Cllorf96, AC02627E1, C8orf31, LINC01203, C1QTNF9, NBEAP1, AC137936.1, AC233280.1, COX17P1, AL513190.1, UBE2V2P1, AP002340.1, KXD1, AC022535.1, AC009656.1, OR10AH1P, MIR1293, AC106872.3, TDRD1, AC107032.1, AC020779.1, VSTM2L, AC092979.1, AC002398.1, RNU6-1300P, IDO2, AC023302.1, AL022097.1, CR381670.1, EXOSC10-AS1, AC010884.2, RNU4-86P, PDZRN4, BOLA2B, AC012409.1, MALL, UGT2B15, SNRPEP2, TRMT112P6, LINC02293, PNP, CCDC81, AC139495.3, DSG3, AC139530.1, Z92544.2, AC091180.2, AC078785.2, AC116348.1, ZNF137P, LRAT, CD22, RPL23AP48, AL031651.2, AC106037.1, RPL35AP30, AC115618.1, SNRPFP1, FHAD1, RPLP1P10, ESMI, CYP4F2, RNU6-1216P, HNRNPCP2, FSD1, NOX4, AC089985.1, PFN1P1, VNN1, AP003035.1, AL139011.2, ARPC1B, AC005332.1, AC139887.4, RPL5P1, LINC01344, PRSS2, AL162734.1, SNORA80E, RPL7AP14, LLGL1, AC009974.1, AC091868.2, AL139118.1, ASB16, RPL7P1, SLC26A4-AS1, RNU6-892P, SMARCE1P5, AC004672.2, AP000879.2, REG3A, AC106820.2, ARL13A, FDPSP5, AC007160.1, RAMP2-AS1, COX6A1P2, RPS17, AC011453.1, TOMM20P4, AP001784.1, PLP2, FELL1, RNU6-90P, AC005392.2, TUBA3FP, LEXM, AL591845.2, ZNF726, AL355432.1, RNU1-73P, AC009063.3, AL590682.1, PSORS1C3, AC025262.2, AL391839.1, AC115837.1, DEFA6, AC006059.4, RPL39P38, WNT2, WDR17, RPL32P1, MORF4, TNNT1, AC022960.1, PIPOX, MIER2, AL138701.1, SNX32, ELOA2, U52111.1, AC007728.2, AC008945.2, AC012494.2, SHISA8, AL020995.1, RN7SL204P, SAG, CFAP99, TREM1, LINC00470, KIAA2012-AS1, SEMG1, CEACAM22P, HMGB1P21, KRT1, AC090666.1, AP003969.2, NR1I3, CNMD, SCNN1G, ASIC4, NUSAP1, IGLC3, CPB1, YBX1P6, IGHGP, PSMA6P1, CCR9, ODCP, AC092135.3, RN7SL211P, RNA5SP492, AC007387.3, AC122688.4, AC130456.4, AL590383.1, LINC00944, SLIT1, RNA5SP466, TPT1P4, AC005180.2, DHRS2, HLA-DQA2, AC110619.1, CSF3, AC074044.1, AC084125.2, FTH1P8, AC109322.2, AL592146.2, AC073842.2, PTMAP4, AC018553.2, PTP4A1P6, AC074029.1, RPS29P29, KRTAP5-9, AC126178.1, SNORD3B-1, DEFB109D, LINC02359, RNU6-204P, SNORD63, AC106028.2, YPEL4, EEF1A1P3, STAG3L3, AC093158.1, AC020604.1, FAM106A, PSCA, RDM1P3, RN7SL602P, EAF1-AS1, AC027763.1, RPS27P25, CCBE1, AC007458.1, SP100, IGKV4-1, AP3B2, PTPRVP, NOC2LP1, RPL35AP32, LINC02616, AC090740.1, AC023202.1, AC022874.1, PTMAP11, GRM4, SOX2, AC064801.2,

[1065]

[1066] Table 57: A2-2 list (only with protein coding)

[1067]

[1068] Table 58: A2-1 list (only with ncRNA without protein coding)

[1069]

[1070] AC090220.1, LINC02023, AC090181.2, AP000777.3, AC073525.1, AL136115.2, AC121493.1, AC073896.4, AL353804.1, Z83843.1, RF00272_2, RF00272_6, RF00272_5, RF00272_4, RF00272, RF00272_7, RF00272_3, AC016876.2, SNORA67, SN0RA71B, AC007952.4, SN0RD3D, SNRK-AS1, S0S1-IT1, RF00012_45, SN0RD3G, RF00012_37, RF00012J8, RF01848, RF00012_31, RF00012J2, RF00012_40, RF00012J6, RF00012_5, RF00012_8, RF00012_46, RF00012_25, RF00012_35, RF00012_50, RF00012_43, RF00012_29, RF00012J3, SN0RD3H, RF00012_26, RF00012_23, RF00012J7, RF00012_30, RF00012_51, RF00012_42, RF00012_48, RF00012_27, RF00012 1, RF00012_2, RF00012_20, RF00012J7, RF00012_32, RF00012_3, RF00012, RF00012_36, RF00012J4, RF00012_21, RF00012_39, RF00012_38, SN0RD3J, RF00012_41, RF00012_47, RF00012J5, RF00012_33, RF00012_22, RF00012_4, RF00012_6, RF00012_44, PCAT18, RF00012_34, VIM-AS1, RF00019_90, RF00019_83, RF00019_94, RF00019_394, RF00019_324, RF00019J83, RF00019_80, RF00019_330, RF00019_654, RF00019_69, RF00019 67, RF00019_270, RF00019_625, RF00019 97, RF00019_581, RF00019 96, RF00019_601, RF00019_708, RF00019_584, RF00019_64, RF00019_319, RF00019_131, RF00019_320, RF00019_555, RF00019_566, RF00019_564, RF00019_724, RF00019_754, RF00019_215, RF00019_72, RF00019_332, RF00019_28, RF00019J91, RF00019J08, RF00019_63, RF00019_214, RF00019_458, RF00019_545, RF00019_417, RF00019_441, RF00019_656, RF00019_513, RF00019_534, RF00019_459, RF00019 11, RF00019_42, RF00019J740, RF00019_250, RF00019 87, RF00019_457, RF00019_47, RF00019_598, RF00019_689, RF00019_321, RF00019_682, RF00019_257, RF00019_412, RF00019_560, RF00019_429, RF00019_677, RF00019_752, RF00019_35, RF00019_648, RF00019_578, RF00019 93, RF00019_678, RF00019J61, RF00019_738, RF00019_208, RF00019 1, RF00019_592, RF00019_653, RF00019_508, RF00019_397, RF00019_435, RF00019_303, RF00019_744, RF00019_54, RF00019_521, RF00019_382, RF00019_328, RF00019_638, RF00019_135, RF00019_99, RF00019_378, RF00019_36, RF00019J68, RF00019J81, RF00019_504, RF00019_542, RF00019J45, RFOOO19J533, RNY1P16, RF00019_363, RF00019_590, RF00019_274, RF00019_428, RF00019_357, RF00019_271, RF00019_226, RF00019_170, RF00019_515, RF00019_594, RF00019_703, RF00019_524, RF00019_484, RF00019_256, RF00019J78, RF00019_544, RF00019_73, RF00019J25, RF00019_485, RF00019_238, RF00019_384, RF00019J80, RNY1P10, RF00019_251, RF00019_482, RF00019_272, RF00019_91, RF00019_21, RF00019_24, RF00019_333, RF00019 13, RF00019_406, RF00019_335, RF00019_364, RF00019_243, RF00019J30, RF00019J711, RF00019_22, RF00019_348, RF00019_376, RF00019_750, RF00019_211, RF00019_229, RF00019_159, RF00019_603, RF00019_409, RF00019_442, RF00019_563, RF00019, RF00019_554, RF00019_472, RF00019_370, RF00019_231, RF00019_645, RF00019_235, RF00019_17, RF00019_596, RF00019 60, RF00019_371, RF00019_748, RF00019_444, RF00019J21, RF00019_404, RF00019_694, RF00019_220, RF00019_26, RF00019_529, RF00019JS91, RF00019_38, RF00019_650, RF00019_518, RF00019_753, RF00019_451, RF00019_15, RF00019_541, RF00019_239, RF00019_471, RF00019 19, RF00019_488, RNY1P11, RF00019_665, RF00019J736, RF00019_342, RF00019_308, RF00019_373, RF00019_l 17, RF00019J79, RF00019_733, RF00019_671, RF00019J01, RF00019_203, RF00019_317, RF00019_326, RF00019_427, RF00019_393, RF00019_647, RF00019J713, RF00019_396, RF00019_344, RF00019_692, RF00019_298, RF00019_622, RF00019J77, RF00019_137, RF00019_628, RF00019_207, RF00019_640, RF00019_314, RF00019_553, RF00019_288, RF00019_702, RF00019 62, RF00019_436, RF00019J74, RF00019_512, RF00019_367, RF00019_611, RF00019_398, RNY3P11, RF00019_535, RF00019_480, RF00019_255, RF00019_93, RF00019_575, RF00019_244, RF00019_705, RF00019_258, RF00019_225, RF00019_383, RF00019_385, RF00019_37, RF00019_688, RNY1P12, RF00019_41, RF00019_346, RF00019_283, RF00019_87, RF00019_586, RF00019J82, RF00019_684, RF00019_481, RF00019_619, RF00019_151, RF00019_310, RF00019_570, RF00019_l 12, RF00019_630, RF00019_520, RF00019_610, RF00019_359, RF00019_526, RF00019_466, RF00019_294, RF00019_487, RF00019_218, RF00019_660, RF00019_415, RF00019_672, RF00019_538, RF00019_263, RF00019_5, RF00019_100, RF00019_56, RF00019_473, RF00019_623, RF00019_577, RF00019J717, RF00019_595, RF00019_316, RF00019_574, RF00019_277, RF00019_410, RF00019_418, RF00019_469, RF00019_209, RF00019_139, RF00019_302, RF00019_97, RF00019J44, RF00019_467, RF00019_587, RF00019_153, RF00019_627, RF00019_624, RF00019_201, RF00019_368, RF00019_60, RF00019_75, RF00019_154, RF00019_685, RF00019_514, RF00019_456, RF00019_511, RNY4P34, RF00019 146, RF00019 325, RF00019 509, RF00019 585, RF00019 579, RF00019_329, RF00019_252, RF00019_278, RF00019_712, RF00019J32, RF00019_620, RF00019_483, RF00019_527, RF00019J57, RF00019_476, RF00019_202, RF00019_707, RF00019J716, RF00019_269, RF00019_490, RF00019 22, RF00019 6, RF00019_92, RF00019J07, RF00019_642, RF00019_375, RNY1P13, RF00019_649, RF00019_434, RF00019_626, RF00019 706, RF00019_643, RF00019_452, RF00019_430, RF00019_48, RF00019_582, RF00019_617, RF00019_683, RF00019_389, RF00019_503, RF00019_437, RF00019_637, RF00019_44, RF00019_634, RF00019_67, RF00019_366, RF00019_463, RF00019_46, RF00019_71, RF00019_282, RF00019_390, RF00019_387, RF00019 726, RF00019J63, RF00019_510, RF00019_470, RF00019_206, RF00019_88, RF00019_353, RF00019_608, RF00019_230, RF00019 9, RF00019_311, RF00019_276, RF00019_34, RF00019_413, RF00019 729, RF00019_618, RF00019 14, RF00019J755, RNY3P12, RF00019_219, RF00019_350, RF00019_681, RF00019J43, RF00019_306, RF00019_567, RF00019_331, RF00019_297, RF00019J73, RF00019_361, RF00019_29, RF00019_475, RF00019_679, RF00019J95, RF00019_743, RF00019_741, RNY3P13, RF00019_407, RF00019_559, RF00019_609, RF00019_221, RF00019_4, RF00019J720, RF00019J71, RF00019_264, RF00019_734, RF00019_78, RF00019_669, RF00019J29, RF00019_704, RF00019_558, RF00019_517, RF00019_236, RF00019_411, RF00019 47, RF00019J728, RF00019_57, RF00019_450, RF00019J737, RF00019_45, RF00019_52, RF00019_82, RF00019J49, RF00019_727, RF00019_334, RF00019_593, RF00019_228, RF00019_731, RF00019_33, RF00019_543, RF00019J34, RF00019_50, RF00019_680, RF00019J2, RF00019_657, RF00019_261, RF00019_531, RF00019_304, RF00019_550, RF00019_588, RF00019_686, RF00019_474, RF00019_447, RF00019_290, RF00019_495, RF00019_433, RF00019_568, RF00019_212, RF00019_96, RF00019_210, RF00019_549, RF00019J0, RF00019_245, RF00019_695, RF00019 74, RF00019J722, RF00019J723, RF00019_400, RF00019_291, RF00019J23, RF00019J20, RF00019_443, RF00019_539, RF00019J33, RF00019_30, RF00019_205, RF00019_293, RF00019_86, RF00019J719, RF00019_224, RF00019 42, RF00019 88, RF00019 16, RF00019_751, RF00019_327, RF00019_616, RF00019_53, RF00019_136, RF00019_540, RF00019J85, RF00019_337, RF00019_262, RF00019_175, RF00019_666, RF00019_349, RF00019_232, RF00019_419, RF00019_354, RF00019_138, RF00019_530, RF00019_607, RF00019_49, RF00019_241, RF00019_414, RF00019_494, RF00019_561, RF00019_309, RF00019J27, RF00019J725, RF00019_693, RF00019_312, RNY3P14, RF00019_43, RF00019_399, RF00019_664, RF00019_345, RF00019_339, RF00019_498, RF00019_55, RF00019_343, RF00019_227, RF00019_315, RF00019_668, RF00019_237, RF00019_59, RF00019_379, RF00019_299, RF00019_292, RF00019_597, RF00019_281, RF00019_61, RF00019J56, RF00019J746, RF00019_519, RF00019_721, RNY1P14, RF00019_377, RF00019J94, RF00019_267, RF00019J52, RF00019_186, RF00019_576, RF00019_501, RF00019J28, RF00019_362, RF00019_39, RF00019_569, RF00019_351, RF00019_246, RF00019_546, RF00019_532, RF00019_295, RF00019_322, RF00019_254, RF00019_612, RF00019 18, RF00019_667, RF00019_340, RF00019_84, RF00019_336, RF00019_405, RF00019_446, RF00019_580, RF00019_557, RF00019_614, RF00019_547, RF00019_260, RF00019_613, RF00019J7, RF00019_395, RF00019_401, RF00019_465, RF00019_562, RF00019_392, RF00019J718, RF00019J70, RF00019_709, RF00019_216, RF00019_489, RF00019_20, RF00019J745, RF00019 69, RF00019_492, RF00019_491, RF00019_591, RF00019_32, RF00019_403, RF00019_300, RF00019_365, RF00019_522, RF00019_391, RF00019J66, RF00019_551, RF00019_249, RF00019_710, RF00019_606, RF00019_556, RF00019J735, RF00019_352, RF00019_431, RF00019_675, RF00019_571, RF00019_259, RF00019J742, RF00019_89, RF00019_548, RF00019_670, RF00019 8, RF00019 58, RF00019_95, RF00019_516, RF00019_502, RF00019_240, RF00019_646, RF00019J09, RF00019_533, RF00019_602, RF00019_453, RF00019_273, RF00019_65, RF00019J749, RF00019_253, RF00019_468, RF00019J02, RF00019_192, RF00019_461, RF00019_386, RNY4P36, RF00019J72, RF00019_62, RF00019_478, RF00019_445, RF00019J03, RF00019J77, RF00019_497, RF00019_347, RF00019_98, RF00019_493, RNY1P15, RF00019_374, RF00019_323, RF00019_81, RF00019_714, RF00019 04, RF00019_644, RF00019_369, RF00019 05, RF00019_486, RF00019_381, RF00019_3, RF00019J40, RF00019J76, RF00019J84, RF00019_523, RF00019_338, RF00019_605, RF00019_687, RF00019_440, RF00019_265, RF00019_266, RF00019_573, RF00019_287, RF00019_464, RF00019_662, RF00019 10, RF00019_318, RF00019_341, RF00019 15, RF00019 715, RF00019_674, RF00019_27, RF00019_248, RF00019_213, RF00019J06, RF00019 76, RF00019J732, RF00019J89, RF00019_604, RF00019 280, RF00019 641, RF00019 506, RF00019 525, RF00019 289, RF00019 698, RF00019_223, RF00019_499, RF00019_380, RF00019_233, RF00019_448, RF00019_739, RFOOO 19_697, RF00019 48, RFOOO 19_505, RFOOO 19_635, RFOOO 19_6, RFOOO 19_360, RF00019_701, RFOOO 19_659, RFOOO 19_307, RFOOO 19_200, RFOOO 19_507, RF00019_79, RFOOO 19_455, RF00019_275, RF00019_31, RF00019_651, RF00019_589, AC009812.1, RF00019_454, RFOOO19 756, RF00019_416, RNY4P37, RF00019_305, RF00019_652, RFOOO 19_420, RFOOO 19_747, RFOOO 19_9, RNY3P15, RFOOO 19_655, RNY3P16, RF00019_234, RF00019_204, RF00019_572, RF00019_673, RF00019_247, RF00019_438, RF00019_358, RF00019_2, RF00019_496, RF00019_68, RF00019_313, RF00019_536, RF00019_51, RF00019_402, RF00019_621, RF00019_449, RF00019_439, RF00019_462, RF00019_356, RF00019J4, RF00019_730, RF00019_528, RF00019_296, RF00019J50, RFOOO 19_164, RFOOO 19_58, RFOOO 19 615, RFOOO 19_85, RFOOO 19_124, RFOOO 19 217, RF00019J65, RF00019_537, RF00019_372, RF00019_40, RF00019_388, RF00019_583, RFOOO 19_25, RFOOO 19_8, RFOOO 19_658, RFOOO 19_66, RFOOO 19_126, RFOOO 19_599, RFOOO 19_479, RFOOO 19_432, RFOOO 19_198, RFOOO 19_477, RFOOO 19_500, RFOOO 19_155, RF00019_663, RF00019_222, AC010542.4, AC115989.1, RF00019_23, RF00019_690, RF01210J5, SNORD13E, RF01210, RF01210_21, RF01210J2, RF01210_26, RF01210_3, RF01210_7, RF01210_30, SNORD13P1, RF01210J3, RF01210_24, RF01210_23, RF01210_8, RF01210_20, RF01210_4, RF01210_22, RF01210_2, RF01210_28, RF01210J0, RF01210_27, RF01210J9, RF01210_25, SNORD13D, RF01210J4, RF01210_6, RF01210_29, RF01210J8, RF01210J7, SNORD13P3, RF01210_9, RF01210 1, RF01210_5, LINC01998, RF01210J6, MIR559, IGHGP, AC000111.2, AC002075.2, AC005042.1, AC007041.1, AC007386.1, AC008427.1, AC009263.1, AC010733.1, ACO 16712.1, RPS29P8, RPL26P 19, AC069154.1, AC079250.1, AC092106.1, RPL22P 16, RPS29P3, NDUFB9P2, EEF1B2P6, AC098824.1, AC104306.1, AC105402.1, AFG3L2P1, AC009487.2, ANKRD26P4, ANP32C, AP000563.1, ATP5PDP1, BTF3P4, BTF3P6, BZW1P1, CASC4P1, CTAGE7P, AC026403.1, AC011411.1, AC020898.1, PRR13P5, RPL10P9, AC008813.1, AC010627.1, RPL10P16, AC026436.1, AC105245.1, AL133241.1, AC091874.1, AP002353.1, EEF1B2P3, EEF1GP1, H3F3AP4, HMGN2P5, HNRNPKP2, HSPA9P1, IP08P1, LDHBP1, LSM12P1, NACAP2, NAP1L4P3, NDUFB1P2, NPM1P27, PA2G4P4, PABPC1P3, PABPC1P4, PAIP1P1, POLR2KP1, PRPF38AP2, PSMA2P3, PTGES3P4, PTP4A2P2, AL139174.1, AL136968.2, AL137784.1, AL049779.2, AL137077.1, RPL12P20, AP006296.1, AL513175.1, HSPD1P4, AC087879.1, AC092045.1, AC011939.1, RPL7AP50, AC138392.1, WHSC1L2P, AL445433.1, AC027237.2, RPSAP12, AL596448.1, AC091153.1, AC079601.2, AC024995.1, RPS15AP29, AC061965.1, AC074051.1, AC074051.4, AC007688.1, RPL23AP42, AC 115223.1, AC024293.1, PRXL2AP2, SRPK2P, RPS19P7, AC091959.1, AL365496.1, RPS3AP38, AC008026.2, AC012170.1, AC091042.1, AC019227.1, AL356535.1, AL589826.1, AC090525.2, AC099560.2, AC020629.1, AC108688.1, AL358178.1, AC135178.6, AC012569.1, AP002812.1, AC026477.1, AL049869.1, AC113935.1, AL022718.1, AL353691.2, AL137845.1, RPL10AP6, RPL12P4, RPL13AP5, RPL21P119, RPL23AP2, RPL24P8, RPL31P12, RPL31P2, RPL34P27, RPL34P33, RPL35P5, RPL37P15, RPL37P2, RPL4P5, RPL5P34, RPL7AP66, RPL7P13, RPL7P9, RPL9P18, RPS10P27, RPS15AP6, RPS19P3, RPS23P8, RPS26P31, RPS2P46, RPS3AP6, RPS7P1, RPS7P11, SEPT10P1, SMARCE1P5, SNRPEP2, SP3P, SUCLG2P2, TERF1P5, TLK1P1, TLK2P1, UBE2V1P2, UBE3AP2, USP8P1, YWHAEP5, YWHAZP2, YWHAZP3, ZBTB8OSP2, ZNF204P, ZNF33BP1, ZNF90P1, CAP2P1, HMGB1P5, AC063950.1, RPL13AP3, STAG3L2, SUGT1P3, BRAFP1, HERC2P10, SMG1P6, MTCO2P12, IGHA2, IGHG3, IGLC7, IGHV3-74, TRAJ18, ATE1-AS1, RN7SKP124, RN7SKP35, RN7SL151P, RN7SL180P, RN7SL735P, RN7SL767P, AL049697.1, AC114490.2, AC090360.1, ANP32BP1, GOLGA2P7, AC012651.1, AC010203.1, TAS2R64P, RNA5SP195, RNA5SP217, CCT6P3, CYP2B7P, RNU1-109P, RNU2-5P, RNU2-6P, RNU4ATAC, RNU6-1138P, RNU6-181P, RNU6-182P, RNU6-20P, RNU6-212P, RNU6-242P, RNU6-251P, RNU6-272P, RNU6-343P, RNU6-414P, RNU6-444P, RNU6-540P, RNU6-570P, RNU6-61 IP, RNU6-638P, RNU6-658P, RNU6-920P, RNU6-957P, RNU6-998P, RNU7-40P, SCARNA13, SCARNA3, SCARNA4, SCARNA7, SNORA31, RF00322 9, RF00322_16, RF00322_5, RF00322_8, RF00322_18, RF00322_26, RF00322J1, RF00322_14, RF00322_10, RF00322_25, RF00322_17, RF00322_9, RF00322, RF00322_3, RF00322_22, RF00322_24, RF00322J3, RF00322_21, RF00322_4, RF00322_2, RF00322_12, RF00322_15, RF00322_20, RF00322_23, RF00322_6, RF00322J7, SNORA36B, SNORA38, RF00428, SNORA53, RFOOO91J5, RF00091, RF00091_2, SNORA62, RF00091_5, RF00091_3, RF00091_4, SNORA71D, SNORA75B, SNORA75, RF00072 2, RF00072, RF00072 3, RF00072 5, RF00072 4,

[1071]

[1072] Table 59: markers only B list

[1073]

[1074] Table 60: markers in common between A2 and B lists

[1075]

[1076] Table 61: Number of Common genes between sets Cl C2 C:i

[1077] Cl 1149 436 Lili

[1078] C 136 633 226

[1079] C3 156 22(i 370

[1080] Table 62: Cl list

[1081]

[1082] KIF9, KISS1R, KLF16, KLHL31, KLHL35, KLK10, KLK12, KPNA2, KRT18, KRT23, KRT80, LAGE3, LCN2, LDHA, LDLRAD3, LEMD1, LGR5, LIF, LING 01124, LIPG, IMNB2, LRP11, LRP4, LRP8, LRRC36, LRRC61, LRWD1, LURAP1L, LY6E, LYPD6, MACC1, MAD2L1, MANEAL, MAP1S, MAPRE1, MARCKSL1, MAT1A, MCM10, MCM3, MCM4, MCM6, MDFI, MDK, MEGF6, LY6G6F-LY6G6D, MELK, MEST, MET, CSKMT, MEX3A, MELTF, MGAT5, MIPEP, MKI67, MMP1, MMP10, MMP11, MMP12, MMP3, MMP7, MND1, MORC2, MORC4, MRPL20, MRPL50, MSLN, MSX1, MSX2, MTFR2, MTHFD1L, MTHFD2, MUC5B, MYBBP1A, MYBL2, MYC, MYCN, MYEOV, MYOM3, MYT1, MZT1, EEF1AKMT1, NANOS3, NANP, NCAPG, NCAPG2, NCAPH, NCOA7, NDUFA4L2, NEBL, NEK2, NETO2, NFE2L3, NINJ2, NKD1, NKD2, NLE1, NME1, NOB1, NOD2, NOLC1, NONO, NOP16, NOP58, NOTUM, NPFFR1, NPIPA1, NPM1, NPM3, NPW, NR2C2AP, NT5DC2, NUF2, NUFIP1, NUP188, NUP62CL, NUTF2, NXT1, NXT2, OAS2, OAS3, ODC1, OLA1, OLFM4, OPRD1, OR51E1, ORC6, OST4, OTUB2, OTX1, OXGR1, P4HA1, PABPC1L, PABPC3, PAFAH1B3, PAH, PAICS, PAK6, PALB2, PALD1, PARPBP, PARVB, PBK, PCDHB13, PCGF2, PCID2, PCNA, PCSK1, PCSK9, PDCD2L, PDCD5, PDCL, PDE10A, PDPN, PDZK1IP1, PERP, PES1, PEX12, PFDN2, PFDN4, PGK1, PHB2, PHF19, PHLDA1, PHLDA2, PI3, PIEZO 1, PIWIL1, PKM, PLAGL2, PLAN, PLCB1, PLEKHB1, PLEKHG4, PLK1, PLK4, PMAIP1, PMEPA1, PNMA5, POC1A, PODNL1, PODXL, POFUT1, POLA1, POLR1B, POLR1D, POLR3K, POM121C, POMP, PPA1, PPAT, PPIH, PPM1H, PRDX4, PRKDC, PROMI, PROSERI, PROX1, PRPS2, PRR7, PRRG1, PRSS21, PRSS22, PRSS33, PSAT1, PSMA7, PSMD14, PSMG1, PSPH, PTK7, PTP4A3, HACD3, PTPN13, PTPRO, PTTG1, PUS7, QPRT, RAB36, RACGAP1, RAD18, RAD51, RAD51AP1, RAD51AP2, RAE1, RAET1L, RAN, RANBP1, RBP4, RCC1, RCN1, RCOR2, RDM1, REG1A, REG1B, REG4, RFC3, RFC4, RFC5, RFWD3, RFXAP, RHEB, RHPN1, RIPPLY3, RLN2, RMI2, RNF183, RNF219, RNF32, RNF43, RNFT2, LINC02313, AL357033.1, RPA3, RPGRIP1L, RPL10A, RPL12, RPL14, RPL18A, RPL21, RPL22L1, RPL23, RPL23A, RPL29, RPL31, RPL35, RPL37A, RPL39, RPL41, AC004086.1, RPL7A, RPP40, RPS13, RPS15, RPS16, RPS18, RPS19, RPS2, RPS20, RPS21, RPS27A, RPS4X, RPS7, RPSA, RPTOR, RRM2, RRP12, RRP7A, RRP9, S100A11, S100P, SAC3D1, SALL4, SAMD5, SAPCD2, SBK1, SBSPON, SCD, SCLY, SCML1, SERPINB5, SET, SFR1, SGO2, SH3TC2, SHB, SHCBP1, SHISA9, SHMT2, SHROOM4, SIGMAR1, SIM2, SKA1, SKA3, SLC12A2, SLC13A3, SLC17A9, SLC22A11, SLC22A3, SLC27A5, SLC28A3, SLC29A1, SLC2A1, SLC35D3, SLC35E4, SLC38A5, SLC3A2, SLC4A11, SLC5A6, SLC6A14, SLC6A6, SLC7A1, SLC7A11, SLC7A5, SLCO4A1, PRELID3A, SMC2, SMKR1, SMN1, SMOC2, SMS, SMTNL2, SNAI1, SNRPD2, SNRPG, SNTB1, SOD3, SORD, SOX1, SOX8, SOX9, SP5, SP6, SPAG5, SPARC, AC118754.1, SPNS3, SPP1, SPRY2, SPTBN2, SRM, SRPK1, SRPX2, SSB, STC2, STIL, STMN1, STOML2, STOX1, STRA6, STX1A, SULF1, SULT2B1, SUMO1, SUN2, TBC1D30, TCFL5, TCP1, TDGF1, TDO2, TDRD5, TEAD4, TFDP1, TGFBI, TGIF1, THAP10, THY1, TICRR, TIMM8A, TIMP1, TIPIN, TK1, TM9SF4, TMEM132A, TMEM206, TMEM69, TMEM81, TMEM97, TMPRSS13, TMPRSS3, TMPRSS5, TMSB10, TNFRSF10B, TNFRSF11B, TNFRSF12A, TNFSF9, TNNC2, TNNT1, TNS4, TOMM34, TOP1MT, TOP2A, TP53I11, TP53RK, TPX2, TRIB3, TRIM29, TRIM7, TRIM72, TRIP 13, TRMT112, TROAP, TRPM2, TSPAN5, TSPEAR, TTC26,

[1083] TTK, TTYH3, TUBA4A, TUBB, TUBB4B, TXLNG, TXNL4B, U2AF2, UBAP1, UBE2C, UBE2L6, UBE2S, UBE2T, UHRF1, ULBP2, ULBP3, UNG, URB2, USF1, UTP14A, VARS, VMO1, DCAF1, VSNL1, VWA2, METTL27, WDR24, WDR72, WDR90, WNT11, WNT2, XCL1, XKRX, XPOT, XRCC2, YBX1, YEATS4, ZC3HAV1L, ZDHHC12, ZIC2, ZIC5, ZNF239, ZNF367, ZNF469, ZNF511, ZNF572, ZNF695, ZNF697, ZNF792, ZNRF3, ZWILCH, ZWINT

[1084] • 246 NOT protein coding genes with their names are:

[1085] AC004943.3, AC005062.1, AC005256.1,

[1086] AC007405.3, AC007497.1, AC008966.3, AC009005.1, LINC01807, AC010542.5, LINC01819, LINC01811, LINC01594, AC063960.1, AC064836.4, ELFN1-AS1, AC083809.1, AC090116.1, AC091729.3, DARS-AS1, AC133540.1, AP001042.1, AF064858.1, AFAP1-AS1, AL118505.1, AL121895.2, AL 135926.2, AL 136962.1, AL139089.1, AL158064.1, AL161431.1, AL354953.1, AL590483.4, AL591069.1, AP000356.2, TRPM2-AS, AP006748.1, BOK-AS1, CASC19, CEBPA-DT, BX537318.1, CRNDE, AC005162.3, AC010280.1, LINC02253, LINC02254, AC034229.4, LINC02086, AC026740.1, LINC02489, DANCR, DDX11-AS1, DLGAP1-AS2, E2F3-IT1, FAM201A, FEZF1-AS1, GAS5, GAS6-AS1, H19, HAR1A, HULC, AP000553.2,

[1087]

[1088] Table 63: C2 list

[1089]

[1090]

[1091] Table 64: C3 list

[1092]

[1093]

[1094] Table 65: Overlaps

[1095]

[1096] ERCC6L, ESMI, ETS2, ETV4, EVX1, EX01, ERFE, ALKALI, PIMREG, FAM72D, IQANK1, FBXL16, FBXO5, FERMT1, FEZF1, FGFRL1, FGGY, FIBCD1, FOXD1, GAD1, GDF15, GGH, GINS1, GMPR, GNL3, GPR19, GPRC5A, GRIN2B, GRIN2D, GTF2IRD1, GZMB, HES6, HIST1H2BF, HIST1H2BL, HIST3H2A, HMGA1, H0XA9, HOXB6, HOXB8, HS6ST2, HSPA8, HSPE1, IER3, IFI6, IFITM3, CXCL8, INHBA, IPO4, IQGAP3, JPH1, KCNH8, KCTD16, KDELR3, RUBCNL, CEMIP, KIAA1257, KIAA1549, KIF18A, KIF18B, KIF20A, KIF24, KIF2C, KIF4A, KISS1R, KLF16, KLK10, KLK12, KPNA2, KRT23, KRT80, LCN2, LEMD1, LGR5, LIF, LINC01124, LIPG, LMNB2, LRP4, LRP8, LRRC36, MAD2L1, MAP1S, MARCKSL1, MDFI, LY6G6F-LY6G6D, MELK, MEST, MET, MEX3A, MELTF, MMP10, MMP12, MMP3, MMP7, MND1, MORC4, MSLN, MSX1, MSX2, MTHFD1L, MYC, MYEOV, MZT1, NANOS3, NCOA7, NDUFA4L2, NEBL, NEK2, NFE2L3, NKD1, NOB1, NOTUM, NPFFR1, NPM1, NPW, NT5DC2, NUF2, NUP62CL, NXT1, ODC1, OLFM4, OPRD1, OST4, OTX1, OXGR1, PAFAH1B3, PBK, PCSK1, PCSK9, PDCD2L, PDZK1IP1, PFDN4, PHLDA1, PHLDA2, PI3, PKM, PLAGL2, PLEKHB1, PLEKHG4, PLK1, PPA1, PPM1H, PRKDC, PROX1, PRSS22, PSAT1, PTP4A3, RACGAP1, RAD51AP2, RAET1L, RAN, RANBP1, RCN1, REG1A, REG1B, REG4, RNF183, RNF43, LINC02313, RPL18A, RPL22L1, RPP40, RPS21, RPSA, RRM2, S100P, SALL4, SAPCD2, SERPINB5, SH3TC2, SKA1, SKA3, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC35E4, SLC6A14, SLC6A6, SLC7A11, SLC7A5, SLCO4A1, SMKR1, SMN1, SNRPG, SORD, SOX1, SOX9, SP5, AC 118754.1, SPP1, STC2, STMN1, TDGF1, TGFBI, TGIF1, TICRR, TMEM132A, TNFRSF10B, TNFRSF11B, TNFSF9, TNNT1, TNS4, TOP2A, TP53I11, TPX2, TRIB3, TRIM29, TRIM7, TRIM72, TRIP13, TRMT112, TTK, TTYH3, TUBB, TUBB4B, U2AF2, UBE2C, UBE2S, UBE2T, UHRF1, ULBP2, ULBP3, USF1, VSNL1, VWA2, WDR72, WNT2, XKRX, YBX1, ZC3HAV1L, ZIC2, ZIC5, ZNF239, ZNF695, ZNF792, ZNRF3

[1097] • 106 NOT protein coding genes with their names are:

[1098] AC005256.1, AC008966.3, AC009005.1,

[1099] LINCO 1807, ACO 10542.5, LINCO 1819, LINCO 1811, ELFN1 -AS 1, AC090116.1, AF064858.1, AFAP1-AS1, AL135926.2, AL161431.1, AL354953.1, AL590483.4, AL591069.1, TRPM2-AS, BOK-AS1, CASC19, CRNDE, LINC02253, LINC02254, LINC02086, LINC02489, DLGAP1-AS2, FEZF1-AS1, GAS5, GAS6-AS1, LINC00659, LINC00858, LINC00920, LINC00970, PURPL, NPSR1-AS1, PLAC4, PRRT3-AS1, AC004080.1, LINC01186, AC093866.1, LINC02163, AC 124067.4, LINCO 1301, BBOX1-AS1, AC007493.1, LINC01411, AC092718.4, AC009065.5, FOXP4-AS1, LINC02432, LINC02542, LINC01703, AC007608.1, AC078993.1, AC099792.1, AC007342.4, AC007342.5, FIRRE, AL365226.2, LINC02418, GATA2-AS1, AL391056.1, PTPRD-AS1, LINC01748, GAPLINC, SLCO4A1-AS1, LINC02657, AL109615.3, LINC02577, SNHG6, SNORD3A, TFAP2A-AS1, VPS9D1-AS1, LINC01315, OGFRP1, ZFAS1, MIR16-2, IGHGP, AC016712.1, RPL26P19, AC026271.1, AC090498.1, AL359075.1, EIF1AXP1, H3F3AP6, HSPD1P1, KRT18P13, AL049873.1, AL441963.1, AC007688.1, HMGB1P6, RPL12P4, RPL34P18, RPS4XP11, RPS7P10, SNRPGP2, IGHG3, AC004009.2, AC007342.9, AC007608.4, RN7SL430P, TDGF1P3, RNU5F-1, SCARNA22, SNORA33, SNORA74D, SNORD46

[1100] 156 common genes between Cl and C3 lists (102 protein coding genes and 54 NOT protein coding genes). In detail:

[1101] • 102 protein coding genes with their names are:

[1102] AGT, APCDD1, ASCL2, AXIN2, BACE2,

[1103] BLACAT1, C2CD4A, C2orf15, C2orf70, CCL20, CCNO, CDH3, CELSR3, CLDN2, CPNE7, CCDC192, CXCL3, CYP4X1, DACH1, DBNDD1, DLX6, DMRTA2, DUSP27, EDAR, ENC1, EPHB2, EPHB3, EPHX4, ETV4, IQANK1, FERMT1, FEZF1, FGFRL1, GDF15, GGH, GRIN2B, GRIN2D, GRPR, HES6, HOXA9, HOXB6, HOXB8, IFI6, KCTD16, CEMIP, KLK10, KLK12, LCN2, LEMD1, LGR5, LINC01124, LIPG, LRRC36, LY6G6FLY6G6D, MET, MMP12, MMP7, MSLN, MSX1, MSX2, NANOS3, NEBL, NKD1, NOTUM, NPFFR1, NPW, OLFM4, OXGR1, PCSK1, PDZK1IP1, PI3, PPM1H, PROX1, RAD51AP2, RAET1L, REG1A, REG1B, RHPN1, RNF183, RNF43, SALL4, SAMD5, SH3TC2, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC6A6, SOX1, SOX9, SP5, SPTBN2, TDGF1, TDRD5, TMPRSS13, TMPRSS5, TNFSF9, TNS4, VWA2, WDR72, XKRX, ZNRF3

[1104] • 54 NOT protein coding genes with their names are: AC009005.1, LINCO 1807, LINCO 1819,

[1105] LINCO 1594, AC090116.1, AP001042.1, AL 158064.1, AL 161431.1, AL590483.4, TRPM2-AS,

[1106] BOK-AS1, CASC19, LINC02253, LINC02254, LINC02086, DLGAP1-AS2, GAS6-AS1, LINC00858, LINC00920, PURPL, NPSR1-AS1, PLAC4, PROX1-AS1, AC093866.1,

[1107] LINC02163, AC124067.4, AC124067.3, AC124067.2, LINC01301, AC007493.1, LINC01411, LINC02432, AC007608.1, AC078993.1, AC099792.1, FIRRE, AC093425.1, GATA2-AS1, LINC01748, GAPLINC, SLCO4A1-AS1, AC104964.1, LINC02595, LINC02577, SNORD3A, TFAP2A-AS1, VPS9D1-AS1, IGHGP, AC090498.1, AL359075.1, AC007608.4, AC018629.1, TDGF1P3, SCARNA22

[1108] 226 common genes between C2 and C3 lists (144 protein coding genes and 82 NOT protein coding genes). In detail:

[1109] • 144 protein coding genes with their names are:

[1110] AGT, AL121761.1, APIP, ART3, ASCL2,

[1111] ASCL5, AXIN2, BACE2, BLACAT1, C17orf77, TEX45, LINC01555, LINC01549, C2CD4A, C2CD4B, C2orf70, CACNA2D2, CADPS, CCDC33, CCL20, CCNO, CDH3, CELSR3,

[1112] CHST4, CLCA1, CLDN2, CPNE7, CCDC192, CXCL1, CXCL3, CYP19A1, CYP4X1,

[1113] DACH1, DBNDD1, DLX6, DMRTA2, DSC3, DUOX2, DUSP27, EDAR, ENC1, EPHB2,

[1114] EPHB3, EPHX4, ETV4, IQANK1, FERMT1, FEZF1, FGFRL1, FZD9, GDF15, GGH,

[1115] GPX2, GRIN2B, GRIN2D, GRM8, HES6, HOXA9, HOXB6, HOXB8, IFI6, IGFL4, ITGA6, KCTD16, CEMIP, KLK10, KLK12, KLK6, KLK7, KLRK1, L1TD1, LCN15, LCN2, LEMD1, LGR5, LGR6, CCDC196, LINC01124, LIPG, LRRC36, LRRIQ4, LY6G6F-LY6G6D, MET, MMP12, MMP7, MSLN, MSX1, MSX2, NANOS3, NEBL, NKD1, NOTUM, NOX1,

[1116] NPFFR1, NPW, OLFM4, OXGR1, PCSK1, PDZK1IP1, PF4, PI3, PKD1L3, PLA2G4D,

[1117] PLCB4, PPM1H, PRKCG, PROX1, RAD51AP2, RAD54B, RAET1L, RASSF10, REG1A,

[1118] REG1B, REN, RETNLB, RNF183, RNF43, AC005833.1, AC027808.2, SALL4, SERPINA1, SH3TC2, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC5A8, SLC6A6, SLCO1B3,

[1119] SLCO5A1, SOX1, SOX9, SP5, SPINK4, TBX18, TCN1, TDGF1, TMEM211, TNFSF9,

[1120] TNS4, VWA2, WDR72, XKRX, ZNRF3

[1121] • 82 NOT protein coding genes with their names are:

[1122] AC002057.2, AC005307.1, FSIP2-AS2,

[1123] AC009005.1, LINC01807, AC010378.2, AC016735.1, LINC01819, AC090116.1, AC104088.2, AC104088.3, AC144450.1, AL161431.1, AL354743.2, AL589669.1, AL590483.4, LINC01659, TRPM2-AS, ARHGEF38-IT1, BOK-AS1, CASC19, CASC8, CASC9, AC022101.1,

[1124] LINC02253, LINC02254, LINC02086, CYP4A22-AS1, DLGAP1-AS2, DLX6-AS1, GAS6-AS1, AC004034.1, AL133297.2, LINC00853, LINC00858, LINC00920, PURPL, LINC01730, MIR3142HG, NPSR1-AS1, PLAC4, AC093866.1, SLC12A9-AS1, LINC02163, AC124067.4, LINC01301, AC007493.1, AL590438.1, LINC01411, LINC02432, AC007608.2, AC007608.1, AC239800.2, AP005271.1, AC078993.1, AC099792.1, LINC02562, FIRRE, GATA2-AS1, AL606537.1, AC036176.3, AC090371.2, LINC01748, GAPLINC, LINC01833, SLCO4A1-AS1, LNCTAM34A, LINC01357, AL022068.1, LINC02577, SNORD3A, TFAP2A-AS1, VPS9D1-AS1, IGHGP, AC090498.1, AL359075.1, KDELC1P1, RPL17P36, SETD6P1, AC007608.4, TDGF1P3, SCARNA22

[1125] 137 common genes between Cl, C2 and C3 lists

[1126] 137 common genes between Cl, C2 and C3 lists (93 protein coding genes and 44 NOT protein

[1127] coding genes). In detail:

[1128] • 93 protein coding genes with their names are:

[1129] AGT, ASCL2, AXIN2, BACE2, BLACAT1, C2CD4A, C2orf70, CCL20, CCNO, CDH3, CELSR3, CLDN2, CPNE7, CCDC192, CXCL3, CYP4X1, DACH1, DBNDD1, DLX6, DMRTA2, DUSP27, EDAR, ENC1, EPHB2, EPHB3, EPHX4, ETV4, IQANK1, FERMT1, FEZF1, FGFRL1, GDF15, GGH, GRIN2B, GRIN2D, HES6, HOXA9, HOXB6, HOXB8, IFI6, KCTD16, CEMIP, KLK10, KLK12, LCN2, LEMD1, LGR5, LINC01124, LIPG, LRRC36, LY6G6F-LY6G6D, MET, MMP12, MMP7, MSLN,

[1130] MSX1, MSX2, NANOS3, NEBL, NKD1, NOTUM, NPFFR1, NPW, OLFM4, OXGR1,

[1131] PCSK1, PDZK1IP1, PI3, PPM1H, PROX1, RAD51AP2, RAET1L, REG1A, REG1B,

[1132] RNF183, RNF43, SALL4, SH3TC2, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC6A6,

[1133] SOX1, SOX9, SP5, TDGF1, TNFSF9, TNS4, VWA2, WDR72, XKRX, ZNRF3

[1134]

[1135] Table 66: C4, C5, C6 lists and overlaps

[1136]

[1137] RPS6KA5, RUNDC3B, S100G, SARNP, SCARA5, SCGB2A1, SCIMP, SCN9A, SCNN1B, SCUBE2, SELENBP1, SEMA3F, SEMA6A, SEPT1, SERTAD4, SGK2, SHC2, SHROOM1, SI, SIDT1, SLC15A2, SLC17A1, SLC17A4, SLC19A3, SLC22A1, SLC22A23, SLC25A34, SLC26A3, SLC26A4, SLC26A6, SLC26A8, SLC28A2, SLC29A4, SLC2A4, SLC30A10, SLC30A4, SLC3A1, SLC44A4, SLC4A10, SLC4A4, SLC51A, SLC52A1, SLC5A5, SLC5A8, SLC9A2, SLC9C1, SLCO4C1, SMCR8, SMIM14, SNAI3, SNX32, SOWAHB, SPECC1, SPINK2, SPTLC3, SRGAP2B, SSTR2, ST3GAL4, ST6GALNAC6, STAP2, STAR, STMN2, STOX2, SUCLG2, SULT1A1, SULT1A2, SULT1B1, SYT10, SYTL2, SYTL5, TAP1, TBX2, ELOA2, TCN2, TEF, THBS3, TINCR, TLR5, TMC4, TMEM100, TMEM14EP, TMEM220, TMEM225, TMEM236, TMEM35A, TMEM37, TMEM44, TMEM72, TMEM82, TMEM87B, TMEM88, TMPRSS15, TMSB4Y, TP53I3, TPH1, TRHDE, TRIM16L, TRIM34, TRIM58, TRPA1, TRPC6, TRPM4, TRPM6, TSHR, TSPAN7, TSSK6, CFAP70, TTC6, TTLL3, TTLL6, TYMS, UBE2L5, UGT1A7, UGT1A1, UGT2B15, UGT2B17, UPK3A, URAD, USP2, VAT1L, VIPR1, VSIG2, VSTM2A, WDR74, WDR78, WIPI1, WNK4, WSCD1, XDH, YJEFN3, ZBTB16, ZBTB7C, ZG16, ZMAT1, ZNF334, ZNF385C, ZNF483, ZNF549, ZNF552, ZNF587, ZNF662, ZNF69, ZNF713, ZNF763, ZNF774, ZNF785, ZNF793, ZNF837 • 623 NOT protein coding genes with their names are:

[1138] AC002398.1, AC002460.2, LINC01531,

[1139] AC002511.2, AC002553.2, AC004158.1, AC004765.1, AC004967.2, AC005220.1, AC005307.1, LINC01843, AC119403.1, AC007182.1, AC007222.1, AC007686.3, AC008982.2, AC009090.6, AC009133.1, AC009163.5, AC009244.2, AC009495.1, AC007098.1, AC009509.4, AC009961.1, SCN1A-AS1, AC010359.2, AC010525.1, AC010623.1, AC010896.1, AC010998.3, AC011416.3, AC011455.6, AC012291.2, AC012358.3, AC012676.4, AC013472.1, AC013553.3, AC015849.3, AC015849.4, AC017006.2, AC017116.2, AC020917.3, AC021148.2, AC022137.4, AC022154.1, AC022267.1, AC022819.1, AC023282.1, AC024236.1, AC024941.2, AC025171.2, AC026202.2, AC026624.1, MIR3936HG, VPS33B-DT, AC069243.1, AC069277.1, AC074008.1, AC083837.1, AC084724.1, AC092171.1, AC092338.4, AC092902.4, AC093827.4, AC093843.2, AC103691.1, AC104162.2, AC104534.1, AC105760.1, AC106045.1, AC106818.2, AC108053.1, AC108471.3, GTF3C2-AS1, AC110611.1, AC115485.1, AC127526.4, AC127526.5, AC128687.3, AC139493.2, AC244100.2, AC253576.2, AD001527.1, ADAMTS9-AS2, AF131216.1, AF165147.1, AF228727.1, AGBL5-IT1, AL022322.2, AL022724.2, AL023882.1, AL033543.1, AL035661.1, AL096794.1, AL 109628.2, AL109840.2, AL121929.3, AL132712.2, AL133245.1, AL133325.3, AL 136090.2, AL 138778.1, AL157394.2, AL157762.1, AL159156.1, AL160272.1, AL365295.1, AL353572.4, AL355388.3, AL450163.1, AL512308.1, AL592295.5, AL731571.1, AP000224.1, LINC01659, AP000439.2, AP000462.2, LINC01687, AATBC, AP001347.1, AP001994.3, AP005210.2, AP005212.4, ARAP1-AS2, ASMTL-AS1, BCYRN1, BRWD1-IT1, CBR3-AS1, CDKN2B-AS1, CFLAR-AS1, AL008582.1, AL021393.1, AC010300.1, LINC02057, AC011472.1, AC011476.3, AC011365.1, AP003059.2, AC008771.1, AL137779.1, AC105020.2, AC016596.1, AC107982.2, AC008870.3, AC008892.1, AC008906.1, AC113383.1, AC103760.1, AC025430.1, LINC02327, AC012317.1, AP002498.1, AC010326.3, AC008467.1, AC008750.5, AC026803.2, AC051619.5, ZNF528-AS1, AC020913.3, ZNF793-AS1, AC124248.1, AC107980.1, AC010618.3, CYP1B1-AS1, DCTN1-AS1, DHRSX-IT1, FAM215B, GLIDR, VSTM2A-OT1, AC246817.1, HEXD-IT1, HMBOX1-IT1, HNF1A-AS1, HOXA11-AS, HOXB-AS4, HAGLR, AP003117.1, LINC00032, LINC00106, LINC00265, LINC00339, LINC00507, LINC00663, LINC00668, LINC00685, LINC00882, LINC00884, LINC00930, LINC00940, LINC01068, LINC01176, LINC02359, LNX1-AS1, MIR194-2HG, MTORAS1, RN7SL715P, AC009022.1, PLCE1-AS1, RABGAP1L-IT1, RBM5-AS1, RC3H1-IT1, RELA-DT, RHOA-IT1, RN7SL832P, AC005280.1, LINC01268, LINC01752, AL121917.1, AC006435.2, AL133330.1, AL118558.3, AL158042.1, AC079610.2, AL137025.1, AL133215.3, AL133215.2, AC098818.2, AL390783.1, AC010834.3, AC103769.1, AC015914.1, AC023421.1, AL162724.2, LINC01570, AC139792.1, AC139795.2, AL162584.1, AC246817.2, AL450344.2, PPP3CB-AS1, AC007272.1, AC106037.1, AC106037.2, LINC01568, AL139383.1, AP005899.1, AC093249.2, AC015813.1, AP002840.2, AC009554.1, AC011933.4, AC107993.1, CARNMT1-AS1, AL 158825.2, AL 136980.1, AC005224.2, AP003119.2, AC092338.3, AC092894.1, AC005833.2, AC027796.1, AL590093.1, AC115102.1, ROR1-AS1, AL451070.1, AC023632.5, LINC01363, AC022075.1, DRAIC, AC092828.1, AC096564.1, AC096564.2, AL 133485.1, LINC02363, AC007906.1, AL 157392.4, AL645568.1, AL731577.1, AC090515.5, AC100821.2, CA3-AS1, LINC02443, LINC02568, LHFPL3-AS2, AC087741.1, AC078777.1, AC019080.3, AC078962.1, RRS1-AS1, AL357093.2, AL357093.1, AC103702.2, AC007496.2, AL596325.2, AC027097.2, AP001554.1, AC009563.1, AC097382.2, LINC02614, AC106791.1, AL591379.1, AC005838.2, AC095057.3, AC067852.3, AC022034.1, AC018552.3, AC009090.1, LINC01206, ACO 10889.1, PLCE1-AS2, AC090970.1, AL591623.1, LINC01341, KCNMA1-AS1, AC073957.3, AC007342.1, AP003086.3, AP002993.1, AC009570.1, FAM3D-AS1, LINC01725, AC009812.3, AC104041.1, AC016355.1, AL603910.1, AL445309.1, AL357568.1, AC012100.2, RNF217-AS1, AC024145.1, AC051619.4, AC025580.2, AC025580.1, AC026979.1, AC027449.1, AP005131.6, AP005131.1, AP005131.7, AL 160286.3, AC006270.1, AC118755.1, AC087501.2, AC069549.1, AC087854.1, AC010768.2, AC092757.2, KLF3-AS1, AC083805.1, AP004608.1, AL157871.5, AC090578.2, AC092375.2, AC022211.3, AC013356.3, AC079174.1, AC040173.1, AC092903.2, AP003170.4, ZFHX2-AS1, AP000866.5, AC123912.4, AC105345.2, PLBD1-AS1, AP002026.1, AC018521.7, AC091231.1, LINC02292, AP000873.4, AC107398.3, LINC02023, AC090559.2, DANT2, AC009163.3, LINC01612, LINC02512, AC135012.1, AC027117.1, SUCLG2-AS1, AP001269.1, AC023389.1, AC139491.2, AC135178.3, AL049835.1, AC007622.2, AP001107.1, AP001033.1, AP001033.2, AL049840.1, AP002812.5, AC009686.2, AC010998.2, AC015908.2, AL136982.3, AC073896.3, BX255925.1, AL138828.1, LINC02012, TNFRSF14-AS1, AC004000.1, AC008147.2, AL031733.2, AL031432.3, AL021707.2, AC004832.5, KAZN-AS1, AL157838.1, AC005520.2, AL022238.2, AL109936.2, AL137856.1, AL135905.1, AC004990.1, AL 139260.1, XACT, RSF1-IT1, SERTAD4-AS1, SIDT1-AS1, SLC26A4-AS1, SNRK-AS1, S0X2-0T, SRD5A3-AS1, STXBP5-AS1, TBC1D22A-AS1, TET2-AS1, THRB-IT1, TMEM9B-AS1, TRG-AS1, TRPC7-AS1, TTTY14, RF00012, U73166.1, VIPR1-AS1, WAC-AS1, XIAP-AS1, LINC01637, AL772337.3, RNY3P14, Z80897.1, ZBTB20-AS4, ZNF346-IT1, ZNF571-AS1, ZNRF3-IT1, MIR1293, AC016601.1, MIR5094, RPL22P21, AC005776.1, AC006042.3, AC007256.1, AC013470.1, AC016894.1, AC091492.1, AC231533.2, CCT8P1, CRYZP1, AC008802.1, EIF2S2P2, HNRNPA1P54, LAMTOR3P2, MTATP8P2, NPM1P40, PGAM1P6, RCC2P6, CR391992.1, AL079342.1, AC007834.2, HMGB1P49, RPL23AP48, AC099336.2, AC005702.2, AC 138392.1, BX679664.3, AC084824.1, AC092868.1, AC027288.2, AC097504.1, AC074051.1, AC099513.1, RPSAP48, AL365475.1, AC026951.1, RPS3AP38, AL445933.1, AC132942.1, AC019227.1, AL354941.1, AC122718.1, AC114324.1, AC126124.2, RPL13AP20, RPL17P43, RPL21P12, RPL38P4, RPL3P13, RPS15AP16, RPS29P12, SETP12, SMARCE1P1, SUDS3P1, EL0CP19, AC092070.2, AC005086.2, AL353898.3, AC004057.1, AC079416.1, AC015910.1, AC009093.8, AP000619.1, AC009093.3, GTF2H2B, SMG1P4, SDHAP3, UBE2Q2P1, MFSD13B, MROH3P, MTCO3P17, AC010086.1, AC104394.1, AC234782.4, DPY19L1P2, FRG1GP, OR5BA1P, OR6M2P, OR7A19P, OR7E91P, AC243562.2, AL117187.1, MTCO1P12, IGHA2, MT-TY, AC002044.2, AC009078.3, AC009135.2, AC009948.4, AC011481.3, AC015920.1, AC020917.4, AC023090.2, AC026523.2, AC027290.2, AC074194.2, AC090373.1, AC092139.3, AC092718.7, AC093642.2, AC105749.1, AC118344.2, AC131212.3, AC131888.1, AC134407.2, AC138470.1, AC233723.2, AL353608.4, AP000437.1, AP001767.4, AP002800.1, AP003072.5, TRGV1, AC104389.4, RN7SKP127, RN7SKP30, RN7SL220P, RN7SL280P, RN7SL308P, RN7SL378P, RN7SL382P, RN7SL559P, RN7SL655P, RN7SL728P, RN7SL76P, RN7SL801P, RNY4P7, AC068896.1, ABCC13, ABCC6P1, AC116562.4, ANKRD20A5P, PGAM1P8, CCDC144CP, HMGB3P22, HMGN2P46, MST1L, NPY6R, PMS2CL, PARGP1, AC098591.1, RPSAP36, CASP17P, TPTEP2, RRN3P3, UPF3AP2, USP32P3, ZNF815P, ZNF321P, RNA5SP464, AC021087.3, CYP2B7P, PI4KAP2, AL355987.4, RNU1-124P, RNU4-2, RNU4-38P, RNU4-62P, RNU4-78P, RNU6-1024P, RNU6-1093P, RNU6-1138P, RNU6-1231P, RNU6-1282P, RNU6-130P, RNU6-137P, RNU6-140P, RNU6-177P, RNU6-181P, RNU6-195P, RNU6-268P, RNU6-272P, RNU6-61 IP, RNU6-657P, RNU6-668P, RNU6-762P, RNU6-890P, RNU6-969P, RNU7-119P, RNU7-40P, RNU7-41P, RNU7-45P, SNORA37, RF00406, RF00409, RF00090, SNORD89, SNORD96B

[1140] 329 genes from C5 list (197 protein coding genes and 132 NOT protein coding genes). In detail:

[1141] • 197 protein coding genes with their names are:

[1142] ABCA8, AC008397.1, SMIM32, ACOT1,

[1143] ACOT2, ADH1C, ADH6, ADTRP, AGPAT4, AHCYL2, AKR1B10, ANPEP, APOB, APOBR, APOC3, APOL4, ARL14, ATP13A4, ATP4B, B3GALT1, BCAP29, BCAS1, BMP5, BOLA2B, BRINP3, BSN, BTNL3, LRMDA, Cllorf86, C15orf48, C3orfl4, CA1, CA2, CACNA2D2, CAMK2A, CAPN13, CCDC152, CCL25, CD163L1, CHMP4A, CIDEC, CKB, CLCA1, CLCA2, CLCA4, CLDN8, CNGA1, CNTN3, CNTN4, CNTNAP3B, COL17A1, COL4A5, COLCA1, CPM, CPS1, CPT1B, CWH43, DHRS9, DNASE1L3, DPF3, DUOX1, DUOX2, DUS4L, EDN3, EFHC2, EGF, ENAM, ENTPD5, FABP1, FAM189A1, FAM3D, FCGBP, FMO5, FOXA1, FOXD2, FRMD3, FSIP2, FUT9, FZD9, GALC, GALNT8, GCNT3, GKN1, GPA33, GPR174, GPT, GRM8, GSTA1, GUCA2B, HAPLN1, HDC, HEPACAM2, HHIP, HMGCS2, HSD17B2, HTR4, IBA57-DT, IL17RE, ISX, ITLN1, KCND3, KCNV1, KIR3DX1, KIT, KLHL7, KLK15, KLK3, KLRC1, KRT20, P3H2, LGALS4, LILRB5, LONRF3, LRRC26, LRRIQ4, LUZP2, LYPD8, MACROD2, MB, MBIP, MGLL, MSMB, MTMR11, MUC17, NAGS, NAT2, NKAIN2, NKX2-1, NOL4, NOS2, NPY1R, NTN4, NXPE1, NXPE4, OIP5, PADI2, PCDHGA10, PDZD4, PDZD9, PIGR, PKIB, PLA2G10, PLA2G2A, PPARGC1A, PTGDR, RAB26, RBFOX1, REP15, RETNLB, RHBDL2, RHEX, NPIPB12, RUNDC3B, S100G, SCARA5, SCNN1B, SELENBP1, SEMA6A, SERTAD4, SGK2, SI, SLC17A4, SLC22A31, SLC26A4, SLC30A4,

[1144] SLC4A4, SLC52A1, SLC5A5, SLC5A8, SLCO1B3, SLITRK6, SMIM5, SPTLC3, ST3GAL4, SULT1A2, SULT1B1, SYTL5, TEF, TINCR, TM4SF4, TMEM100, TMEM150B, TMEM225, TMPRSS15, TPH1, TRPA1, TRPC6, TRPM6, TTLL6, UGT1A1, UGT2B15, UGT2B17, VAT1L, VSIG2, XDH, ZG16, ZNF334

[1145] • 132 NOT protein coding genes with their names are:

[1146] AC002511.2, AC004765.1, AC005307.1,

[1147] AC005550.2, AC007222.1, AC011455.6, AC012358.3, AC013553.3, AC021148.2, AC022267.1, AC024236.1, AC025160.1, AC127526.4, AC253576.2, AD001527.1, AL035661.1, AL132712.2, AL133245.1, AL133325.3, AL157762.1, LINC01687, AATBC, AP005210.2, AP005212.4, ARAP1-AS2, AL008582.1, LINC02057, AC011365.1, AP003059.2, AP002498.1, AC107980.1, DCTN1-AS1, AC246817.1, LINC00265, LINC00486, LINC00520, LINC01068, AL121917.1, AC006435.2, AC079610.2, AL390783.1, LINC01570, AL162584.1, AL512329.2, AC009554.1, AL136980.1, AP003119.2, LINC01363, DRAIC, LINC02363, CA3-AS1, AC019080.3, LINC01206, AL591623.1, AC016355.1, AC084083.1, AC118755.1, AC092757.2, AC013356.3, AC092903.2, AP003170.4, AP002026.1, AC018521.7, LINC02023, DANT2, LINC01612, AC135012.1, AP001269.1, LINC01833, AC009686.2, AC010998.2, AC022364.1, LINC02012, TNFRSF14-AS1, AC008147.2, AL031432.3, AL157838.1, AC005520.2, AL137856.1, AC004990.1, SIDT1-AS1, ST7-AS1, STXBP5-AS1, THRB-IT1, TRPC7-AS1, TTTY14, VIPR1-AS1, Z80897.1, RPL22P21, AC005776.1, PTMAP10, AC231533.2, AC016596.2, AC008802.1, EEF1A1P9, MTATP8P2, AL079342.1, AC007834.2, RPL23AP48, BX679664.3, RPL11P3, RPSAP48, AL389915.1, AL365475.1, AL445933.1, AL354941.1, RPL13AP20, RPL17P43, RPS15AP16, SMG1P4, AC010086.1, IGHA2, IGLC7, MT-TY, AC009135.2, AC092718.7, AL512506.2, AP002800.1, RN7SL382P, AC090004.1, ABCC13, ANKRD20A5P, MST1L, NPY6R, CASP17P, CYP2B7P, RNU4-38P, RNU4-78P, RNU6-1231P, RNU7-119P, RNU7-41P, SNORA37

[1148] 578 genes from C6 list. (187 protein coding genes and 391 NOT protein coding genes). In detail:

[1149] • 187 protein coding genes with their names are:

[1150] AC093323.3, AC110619.1, ADAM23,

[1151] ADHFE1, AMT, ANKFN1, ANO5, APOB, ARGFX, ARHGAP44, ARHGAP8, ARPC1B, ASGR2, ASPA, ASPG, ASXL3, PGGHG, ATOH8, ATP1A2, ATP2A3, ATP4A, B3GNT6, BEST2, C12orf56, LINC01550, C16orf89, STUM, GATD3A, PRR34, CAB YR, CACNA1F, CACNA1H, CADM2, CBLN3, CCDC144A, CCL16, CD160, CHGA, CHGB, CHKB, CHRM1, CLDN11, CLEC18A, CLN3, CNN1, CNTN2, CTRB1, CYB561A3, CYP2C9, CYP46A1, DES, DHRS4, AC024257.3, DNAJB7, DNMT3A, DRD5, DSEL, EDA2R, EMX2, EPB41L4A, EXOC3L4, FAM124A, FAM153A, SAXO1, FAM189A1, FAM219B, FAM81B, FHAD1, FLT3LG, FMN2, FOLR1, FOXP1, FUZ, GPM6A, GPR20, GPT, GRIA4, GTF2H2C, HARBI1, HEPHL1, HES5, HPCA, HSD3B2, HSPA4, HTR4, IFIT1, KANK4, KCNH6, KCNK12, IQCN, KLRK1, LDB3, LINC00923, LIPC, LLGL1, MAN2C1, MASP1, MEP1B, MESP2, MROH7, MRPS24, NBPF8, NEUROD1, NFATC4, NPIPA5, NPIPB11, NPY1R, NR1H4, NRXN1, NTAN1, NWD1, NXPE2, OGDHL, OPRM1, OR1L8, OR8D4, PCDHGA5, PCDHGA8, PHC1, PKDREJ, PKHD1, PLIN5, PRIMA1, PRKCZ, PROZ, PRRG3, PTPRS, PYY, RGS6, RHBDL3, RNASEK, AC069185.1, NPIPB13, ZNF727, RPL10L, RPS6KB2, RRAD, SCRG1, SHISA8, AC027796.3, SLC13A1, SLC14A1, SLC16A11, SLC22A2, SLC25A34, SLC29A4, SLC37A2, SLC3A1, SLC4A1, SLC4A10, SLC51A, SLC6A1, SLC8A3, SMC1B, SNAI3, SPEG, SRGAP2B, STAR, SYNM, SYT2, TAF6, TBKBP1, TBX1, ELOA2, TDRD1, TEKT3, TEX22, TGM4, TMEM63C, TMEM87B, TREH, TRIM58, TTC6, TTLL9, TYMS, UGT1A7, UGT1A1, USHBP1, USP44, WDR17, WSCD1, YJEFN3, ZNF385D, ZNF683, ZNF793, ZNF843, ZSCAN32

[1152] • 391 NOT protein coding genes with their names are:

[1153] AC002128.2, AC002460.2, LINC01531,

[1154] AC005546.1, AC005740.4, AC005899.8, AC005498.3, AC007387.3, AC008073.2, AC009090.6, AC009159.3, AC007098.1, SCN1A-AS1, AC010623.1, AC011287.1, AC011416.3, AC012368.2, AC012676.4, AC013553.3, AC020658.5, AC021683.5, AC024337.2, AC005759.2, AC069243.1, LINC01832, AC073648.7, AC074008.1, AC078883.3, AC090206.1, AC092338.4, AC093843.2, AC097478.3, AC103591.4, AC103691.1, AC104451.1, AC104534.1, AC106045.1, AC108471.3, AC108519.1, AC108704.1, AC115485.1, AC125603.4, AC127035.1, AC139493.2, LINC02251, AF186192.1, AL021918.5, AL033527.4, AL033539.2, AL050350.1, AL096870.10, AL109628.2, AL136090.2, AL159156.1, AL162151.1, AL353151.2, AL353572.4, AL392172.2, AL591163.1, AL592146.2, AL731559.1, AL731566.1, AP000224.1, LINC01687, AP000654.1, AATBC, AP001462.1, AP001994.3, ASH1L-IT1, BRWD1-IT1, CARS-AS1, CASC16, CCDC26, AL021393.1, SEMA6A-AS2, AC003991.2, AC008708.2, AC011442.1, AC011365.1, AC091868.2, AC026412.3, AC105020.2, AC010359.1, AC010624.3, AC107982.2, LINC01859, FAM106A, AC106028.2, LINC02327, AC107241.1, AP003390.2, AC120114.1, AC008467.1, AC008750.5, AC012313.3, ZNF528-AS1, AC020913.1, AC015922.2, AC092296.2, DPYDAS2, EDRF1-AS1, EPHA1-AS1, ERVH48-1, FGF10-AS1, LINC01344, HMBOX1-IT1,

[1155] IGBP1-AS1, AP003354.1, KIF9-AS1, LINC00507, LINC00678, LINC00930, LINC00940, LINC02359, AL844908.1, MYCBP2-AS1, NCBP2-AS1, NEXN-AS1, PCAT7, PLCXD2-AS1, PRKG1-AS1, RBM5-AS1, RHOA-IT1, RN7SL832P, AC004080.2, AL049612.1, AC005280.1, LINC01645, AC027288.3, AC096733.2, AC023421.1, AL731533.2, LINC01570, AC139792.1, AC026391.1, AL450344.2, AC021683.1, AC106037.2, LINC01568, LINC01996, AP005899.1, AC093249.2, AC097059.1, AC124067.3, AC114956.1, AL158834.1, AC011933.4, AC010680.2, CARNMT1-AS1, AL355499.1, AC009656.1, AC092338.3, AC092894.1, AL590093.1, LINC02355, AC125807.2, AC089998.4, AC005828.4, AC108010.1, TTC39A-AS1, AC090260.1, AC096564.2, AC007906.1, AC009063.3, AP001830.1, AL 138921.2, AC084375.1, MAFTRR, AL357093.1, AC103702.2, AC053513.2, AC106791.1, AL591379.1, AC009088.1, AC010735.2, AC022874.1, AC022034.1, AC007448.3, AC104187.1, PLCE1-AS2, AC139887.4, KCNMA1-AS1, AC108749.1, BX088651.4, FAM3D-AS1, LINC01725, AL590723.1, AC104041.1, AL603910.1, AC009754.1, AC091182.2, AP005131.2, AC011825.2, FO393415.1, LINC02593, AC006270.1, AC141002.1, AC007406.3, KLF3-AS1, AC044802.1, AL157871.5, AC104590.1, AL359636.2, AC079174.1, AC087301.1, AC092903.2, AC015712.6, AC105345.2, AC007529.1, AC091231.1, AC066613.1, AC026474.1, AC107896.1, AP000977.1, AC107398.3, LINC02023, AC123567.2, LINC02207, AC022167.2, AC009163.3, AC007378.1, AC022916.1, AC012291.1, AL049835.1, AP001033.1, AC103810.5, AP001021.1, AC010998.2, AL136982.3, AL390961.2, TARID, AL022328.1, AC026765.2, KAZN-AS1, AC005520.2, AC015853.3, MIR646HG, AL353593.2, AC004672.2, SIAH2-AS1, SLC26A4-AS1, SOX2-OT, SSSCA1-AS1, TET2-AS1, TMEM9B-AS1, TRPC7-AS1, TTTY10, RNU1-30P, WAC-AS1, Z98885.3, ZRANB2-AS1, AC112504.1, AP001525.1, MIR1293, MIR3128, AC016601.1, AC008147.4, AC013470.1, BTBD7P1, CR392039.5, CRYZP1, CTBP2P8, AC025459.1, EIF2S2P2, FCF1P7, HMGB1P41, HNRNPA1P54, KLF2P2, LAMTOR3P2, NCLP1, NPM1P40, RAD17P2, RALGAPA1P1, RBBP4P1, RBM22P2, RCC2P6, HMGB1P49, AC145285.1, AC099336.2, AL450338.1, RPL10P2, AC068446.1, RPL7AP15, BNIP3P37, AC093827.3, AC104986.1, AL365475.1, AC026951.1, AL049872.1, AC027763.1, AC107032.1, RPL23AP66, BOLA2P3, AL356273.2, RPL21P12, RPL3P13, UBE2V2P1, YWHAQP5, ZNF90P1, AC005086.3, AC005086.4, PTP4A1P6, AC242376.2, ANKRD20A21P, AP000619.1, AC009093.3, GTF2H2B, AC090950.1, SBDSP1, UBE2Q2P1, UOX, AC090114.3, AC092933.1, AC104394.1, CHMP1B2P, CYP2T3P, OR7A19P, OR7E91P, AC243562.2, AC135352.1, AL589743.2, AL358232.1, AL117187.1, FRG1JP, AC139495.3, IGHG2, MT-TC, AC002094.5, AC007608.4, AC009090.5, AC011481.3, AC015920.1, AC018737.2, AC020658.6, AC020917.4, AC026523.2, AC040160.2, AC073548.1, AC074194.2, AC092139.3, AC093642.2, AC105101.1, AC122688.3, AF001548.3, AL359510.2, AP000437.1, AP001784.1, AP003072.4, AP003969.2, TRGV1, RN7SL1, RF02271, RN7SKP127, RN7SL113P, RN7SL297P, RN7SL308P, RN7SL378P, RN7SL602P, RN7SL655P, RN7SL660P, RN7SL744P, RN7SL801P, RN7SL834P, AC097374.1, AC141586.5, ANO7L1, CEACAM22P, CFL1P1, GUSBP2, HMGB3P22, LINC00933, NPY6R, SH3GL1P1, RNA5SP466, RNU1-73P, RNU4-21P, RNU6-1005P, RNU6-1216P, RNU6-272P, RNU6-28P, RNU6-431P, RNU6-476P, RNU6-657P, RNU6-701P, RNU6-703P, RNU6-762P, RNU6-797P, RNU6-944P, RNU7-57P, RF00406, RF00611

[1156] 292 common genes between C4 and C5 lists (177 protein coding genes and 115 NOT protein coding genes). In detail:

[1157] • 177 protein coding genes with their names are:

[1158] ABCA8, AC008397.1, SMIM32, ACOT1,

[1159] ACOT2, ADH1C, ADH6, ADTRP, AHCYL2, AKR1B10, ANPEP, APOB, APOBR,

[1160] APOC3, ARL14, ATP13A4, ATP4B, B3GALT1, BCAP29, BCAS1, BMP5, BRINP3,

[1161] BTNL3, Cllorf86, C15orf48, CA1, CA2, CACNA2D2, CAMK2A, CAPN13, CCDC152, CCL25, CD163L1, CHMP4A, CKB, CLCA1, CLCA2, CLDN8, CNGA1, CNTN3, CNTN4, CNTNAP3B, COL17A1, COL4A5, COLCA1, CPM, CPT1B, CWH43, DHRS9, DNASE1L3, DPF3, DUOX1, DUOX2, DUS4L, EDN3, EFHC2, EGF, ENAM, ENTPD5, FABP1, FAM189A1, FAM3D, FCGBP, FMO5, FOXA1, FOXD2, FRMD3, FSIP2, FUT9, FZD9, GALC, GALNT8, GCNT3, GKN1, GPA33, GPR174, GPT, GRM8, GSTA1, GUCA2B, HAPLN1, HDC, HEPACAM2, HHIP, HMGCS2, HSD17B2, HTR4, IL17RE, ISX, ITLN1, KCND3, KCNV1, KIR3DX1, KIT, KLHL7, KLK15, KLK3, KLRC1, KRT20, P3H2,

[1162] LGALS4, LILRB5, LONRF3, LRRC26, LRRIQ4, LUZP2, LYPD8, MACROD2, MB,

[1163] MGLL, MSMB, MTMR11, NAGS, NAT2, NKAIN2, NOL4, NPY1R, NTN4, NXPE1, NXPE4, OIP5, PADI2, PCDHGA10, PDZD4, PDZD9, PIGR, PKIB, PLA2G10, PLA2G2A, PPARGC1A, PTGDR, RAB26, RBFOX1, REP15, RETNLB, RHBDL2, RHEX, NPIPB12, RUNDC3B, S100G, SCARA5, SCNN1B, SELENBP1, SEMA6A, SERTAD4, SGK2, SI, SLC17A4, SLC26A4, SLC30A4, SLC4A4, SLC52A1, SLC5A5, SLC5A8, SPTLC3, ST3GAL4, SULT1A2, SULT1B1, SYTL5, TEF, TINCR, TMEM100, TMEM225, TMPRSS15, TPH1, TRPA1, TRPC6, TRPM6, TTLL6, UGT1A1, UGT2B15, UGT2B17, VAT1L, VSIG2, XDH, ZG16, ZNF334

[1164] • 115 NOT protein coding genes with their names are:

[1165] AC002511.2, AC004765.1, AC005307.1,

[1166] AC007222.1, AC011455.6, AC012358.3, AC013553.3, AC021148.2, AC022267.1, AC024236.1, AC127526.4, AC253576.2, AD001527.1, AL035661.1, AL132712.2, AL133245.1, AL133325.3, AL157762.1, LINC01687, AATBC, AP005210.2, AP005212.4, ARAP1-AS2, AL008582.1, LINC02057, AC011365.1, AP003059.2, AP002498.1, AC107980.1, DCTN1-AS1, AC246817.1, LINC00265, LINC01068, AL121917.1, AC006435.2, AC079610.2, AL390783.1, LINC01570, AL 162584.1, AC009554.1, AL 136980.1, AP003119.2, LINC01363, DRAIC, LINC02363,

[1167] CA3-AS1, AC019080.3, LINC01206, AL591623.1, AC016355.1, AC118755.1, AC092757.2, AC013356.3, AC092903.2, AP003170.4, AP002026.1, AC018521.7, LINC02023, DANT2, LINC01612, AC135012.1, AP001269.1, AC009686.2, AC010998.2, LINC02012, TNFRSF14-AS1, AC008147.2, AL031432.3, AL157838.1, AC005520.2, AL137856.1, AC004990.1,

[1168] SIDT1-AS1, STXBP5-AS1, THRB-IT1, TRPC7-AS1, TTTY14, VIPR1-AS1, Z80897.1, RPL22P21, AC005776.1, AC231533.2, AC008802.1, MTATP8P2, AL079342.1, AC007834.2, RPL23AP48, BX679664.3, RPSAP48, AL365475.1, AL445933.1, AL354941.1, RPL13AP20, RPL17P43, RPS15AP16, SMG1P4, AC010086.1, IGHA2, MT-TY, AC009135.2, AC092718.7, AP002800.1, RN7SL382P, ABCC13, ANKRD20A5P, MST1L, NPY6R, CASP17P, CYP2B7P, RNU4-38P, RNU4-78P, RNU6-1231P, RNU7-119P, RNU7-41P, SNORA37

[1169] 207 common genes between C4 and C6 lists (70 protein coding genes and 137 NOT protein coding genes). In detail:

[1170] • 70 protein coding genes with their names are:

[1171] AC 110619.1, ADHFE1, AMT, ANKFN1,

[1172] APOB, ARHGAP44, ARHGAP8, ASXL3, ATOH8, ATP2A3, B3GNT6, BEST2, LINC01550, GATD3A, CCDC144A, CHKB, CLEC18A, CLN3, CYB561A3, DHRS4, DNMT3A, EPB41L4A, EXOC3L4, FAM189A1, FLT3LG, FOXP1, GPM6A, GPT, HSPA4, HTR4,

[1173] IQCN, KLRK1, LINC00923, LLGL1, MAN2C1, MROH7, MRPS24, NBPF8, NPY1R, NR1H4, NTAN1, NWD1, NXPE2, OR8D4, PKHD1, PLIN5, PRRG3, PYY, RGS6,

[1174] RHBDL3, RNASEK, RPL10L, SLC25A34, SLC29A4, SLC3A1, SLC4A10, SLC51A, SNAI3, SRGAP2B, STAR, ELOA2, TMEM87B, TRIM58, TTC6, TYMS, UGT1A7, UGT1A1, WSCD1, YJEFN3, ZNF793

[1175]

[1176] Table 67: Table of number of combinations set based on distinct mode

[1177]

[1178] 6 C3 3711 2112 bis 7 C5 329 197 132 C LVC5 292 177 1 15 9 C2. C3 2 i ■ 1 1 1 "2 J U C LvCU 207 Th 1.-17 1 1 ( ' kVC3 Uh U I2 7 1 12 r kVC2. V C3 137 9.1 I I 1.3 C3. VC 1 52 29 23 1 1 ( '3iV( '(i 31 9 22 15 CI. VC,’ 21 hi

[1179] Ki ( VC hVCV 19 15 1 17 ( ’5. C(1 i s li 12 i s r i.vC5. V( '(i i s 6 12 19 ( '2i C5 II. 1 1

[1180] ii ro.vr i.vrti H; u i n 21 < ‘2.vr i 15 12

[1181] 22 ( uvru.vr i I I 12 2 23 r2. VC3. V r5 I I 9 2 2 1 r2. VC l. Vr5 H l " 2 25 C21,: A C l. VC5 9 " 1 23 C |,\ Cii 1 11 4 27 C2*vCG 2 1 1 2< r i. ui.vrt; 0 2 u r2.v( -3,vn> 2 1 1 311 r i. K C2. ti 1 0 1:’ i r2.vc i.v cti 1 1 0 32 C3.\ ( '5. U ’6 1 0 1 33 C I. VC2X C3A C(i 1 0 1 34 C2.vC3. VC kVC(i 1 1 ll 35 C3CC 1. VC5, V( T, 1 I I 1

[1182] The resulting intersections and combinations are shown in Figure 6.

[1183] REFERENCES:

[1184] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

[1185] 1 Umar, A., Dunn, B. K. & Greenwald, P. Future directions in cancer prevention. Nat Rev Cancer 12, 835-848, doi: 10.1038 / nrc3397 (2012). 2 Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer, doi:10.1038 / s41568-020-0285-7 (2020).

[1186] 3 Ward, J. P., Gubin, M. M. & Schreiber, R. D. The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer. Adv Immunol 130, 25-74, doi:10.1016 / bs.ai.2016.01.001 (2016).

[1187] 4 Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782-795, doi:10.1016 / j.immuni.2013.10.003 (2013).

[1188] 5 Mlecnik, B. et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 29, 610-618, doi: JCO.2010.30.5425 [pii]

[1189] 10.1200 / JC0.2010.30.5425 (2011).

[1190] 6 Kensler, T. W. et al. Transforming Cancer Prevention through Precision Medicine and Immune-oncology. Cancer Prev Res (Phila) 9, 2-10, doi:10.1158 / 1940-6207. CAPR-15-0406 (2016).

[1191] 7 Galon, J. & Bruni, D. Tumor Immunology and Tumor Evolution: Intertwined Histories. Immunity 52, 55-81, doi:10.1016 / j.immuni.2019.12.018 (2020).

[1192] 8 Fox, B. A. et al. Cancer's Dark Matter: Lighting the Abyss Unveils Universe of New Therapies. Clin Cancer Res 29, 2173-2175, doi:10.1158 / 1078-0432. CCR-23-0422 (2023). 9 Laumont, C. M. et al. Noncoding regions are the main source of targetable tumorspecific antigens. Sci Transl Med 10, doi:10.1126 / scitranslmed.aau5516 (2018).

[1193] 10 Merlotti, A. et al. Noncanonical splicing junctions between exons and transposable elements represent a source of immunogenic recurrent neo-antigens in patients with lung cancer. Sci Immunol 8, eabm6359, doi:10.1126 / sciimmunol.abm6359 (2023).

[1194] 11 Angelova, M., Mascaux, C. & Galon, J. Evasion before invasion: Pre-cancer immunosurveillance. Oncoimmunology 10, 1912250, doi: 10.1080 / 2162402x.2021.1912250 (2021).

[1195] 12 Mascaux, C. et al. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature 571, 570-575, doi:10.1038 / s41586-019-1330-0 (2019).

[1196] 13 Meylan, M. et al. Early Hepatic Lesions Display Immature Tertiary Lymphoid Structures and Show Elevated Expression of Immune Inhibitory and Immunosuppressive Molecules. Clin Cancer Res 26, 4381-4389, doi:10.1158 / 1078-0432. CCR-19-2929 (2020). 14 Becker, W. R. et al. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer. Nat Genet 54, 985-995, doi:10.1038 / s41588-022-01088-x (2022).

[1197] 15 Chen, B. et al. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell 184, 6262-6280 e6226, doi: 10.1016 / j. cell.2021.11.031 (2021).

[1198] 16 Roelands, J. et al. Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis. Gut 72, 1326-1339, doi:10.1136 / gutjnl-2022-327608 (2023).

[1199] 17 Cross, W. et al. The evolutionary landscape of colorectal tumorigenesis. N...

Claims

CLAIMS:

1. A method for the treatment of a cancer in a subject comprising administering to the subject a therapeutically effective amount of i) one or more dark antigen(s) and / or ii) one polynucleotide encoding for one or more dark antigen(s) wherein the dark antigen is encoded by one ncRNA selected from Table A.

2. The method of claim 1 for preventing progression of a cancer.

3. The method of claim 1 for preventing the recurrence of a cancer.

4. The method of claim 1 for the prophylactic treatment of a cancer.

5. The method of claim 4 wherein the subject has at least one premalignant lesion.

6. The method according to any one of claims 1 to 5 wherein the dark antigen is a HLA- restricted epitope selected from Tables 1-41.

7. The method of claim 6 wherein the dark antigen is a HLA-A*0201 restricted epitope.

8. The method of claim 7 wherein the dark antigen is a HLA-A*0201 restricted epitope selected from Table 2.

9. The method according to any one of claims 1 to 8 wherein the subject is administered with a cocktail comprising a plurality of HLA-restricted epitopes.

10. The method of claim 9 wherein the cocktail comprises a first HLA-restricted epitope that is capable of being bound by MHC molecules of allele HLA-A*0201 and a second HLA-restricted epitope that is capable of being bound by MHC molecules of allele HLA-A-A*03.

11. The method of claim 9 wherein the cocktail comprises 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12;13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137;138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; 294; 295; 296; 297; 298; 299; 300; 301; 302; 303; 304; 305; 306; 307; 308; 309; 310; 311; 312; 313; 314; 315; 316; 317; 318; 319; 320; 321; 322; 323; 324; 325; 326; 327; 328; 329; 330; 331; 332; 333; 334; 335; 336; 337; 338; 339; 340; 341; 342; 343; 344; 345; 346; 347; 348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 358; 359; 360; 361; 362; 363; 364; 365; 366; 367; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377, or more HLA-restricted epitopes encoded by the ncRNAs selected from Table A or selected from Tables 1-41.

12. The method according to any one of claims 1 to 11 wherein the dark antigen is fused or conjugated to an antibody for forming an immunoconjugate.

13. The method according to any one of claims 1 to 8 wherein the HLA-restricted epitope(s) is / are administered to the patient in the form of one or more polynucleotides encoding the desired HLA-restricted epitopes.

14. The method of claim 13 wherein the HLA-restricted epitopes of the invention are encoded by a single polynucleotide.

15. The method of claim 13 wherein the polynucleotide encode 2; 3; 4; 5; 6; 7; 8; 9; 10; 11;12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153;154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 201; 202; 203; 204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215; 216; 217; 218; 219; 220; 221; 222; 223; 224; 225; 226; 227; 228; 229; 230; 231; 232; 233; 234; 235; 236; 237; 238; 239; 240; 241; 242; 243; 244; 245; 246; 247; 248; 249; 250; 251; 252; 253; 254; 255; 256; 257; 258; 259; 260; 261; 262; 263; 264; 265; 266; 267; 268; 269; 270; 271; 272; 273; 274; 275; 276; 277; 278; 279; 280; 281; 282; 283; 284; 285; 286; 287; 288; 289; 290; 291; 292; 293; 294; 295; 296; 297; 298; 299; 300; 301; 302; 303; 304; 305; 306; 307; 308; 309; 310; 311; 312; 313; 314; 315; 316; 317; 318; 319; 320; 321; 322; 323; 324; 325; 326; 327; 328; 329; 330; 331; 332; 333; 334; 335; 336; 337; 338; 339; 340; 341; 342; 343; 344; 345; 346; 347; 348; 349; 350; 351; 352; 353; 354; 355; 356; 357; 358; 359; 360; 361; 362; 363; 364; 365; 366; 367; 368; 369; 370; 371; 372; 373; 374; 375; 376; 377, or more HLA-restricted epitopes encoded by the ncRNAs selected from Table A or selected from Tables 1-41.

16. The method according to any one of claims 1 to 15 wherein the polynucleotide is a messenger RNA (mRNA).

17. The method according to any one of claims 1 to 16 wherein the polynucleotide is inserted into a vector.

18. The method according to any one of claims 1 to 17 wherein the polypeptide or the polynucleotide is conjugated to at least one other molecule selected from the group consisting of polynucleotides, polypeptides, lipids, lectins, carbohydrates, vitamins, cofactors, and drugs.

19. The method according to any one of claims 1 to 18 wherein the polypeptide or the polynucleotide is formulated using one or more lipid-based structures that include but are not limited to liposomes, lipoplexes, or lipid nanoparticles.

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