Methods of predicting cancer in patients having premalignant lesions

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 early biomarkers and targets for prophylactic immune modulation approaches in individuals at high risk of developing colorectal cancer.

Description

[0001] METHODS OF PREDICTING CANCER IN PATIENTS HAVING PREMALIGNANT LESIONS

[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] DETAILED DESCRIPTION OF THE INVENTION:

[0012] 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 biomarkers and targets for prophylactic immune modulation approaches in individuals at high risk of developing colorectal cancer. Thus, the present invention relates to a method for determining whether a subject is at risk of having a cancer comprising determining the level of at least one ncRNA in a biological sample obtained from the subject and wherein the expression level of the ncRNA correlates with the risk of having cancer.

[0013] In some embodiments, the method of the present invention is particularly suitable for predicting the risk of having a cancer that results from polygenic or multifactorial phenotypes. In some embodiments, the method of the present invention is particularly suitable for predicting the risk of cancer in a subject exposed or previously exposed to exogenous factors such as sun, tobacco, alcohol, pollution, certain chemical, or radiation.

[0014] In some embodiments, the method of the present invention is particularly suitable for predicting a risk 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).

[0015] In some embodiments, the method of the present invention is particularly suitable for predicting the risk of having a colorectal cancer.

[0016] 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).

[0017] As used herein, the term "risk" in the context of the present invention, relates to the probability that an event will occur over a specific time period and can mean a subject's "absolute" risk or "relative" risk. Absolute risk can be measured with reference to either actual observation postmeasurement for the relevant time cohort, or with reference to index values developed from statistically valid historical cohorts that have been followed for the relevant time period. Relative risk refers to the ratio of absolute risks of a subject compared either to the absolute risks of low risk cohorts or an average population risk, which can vary by how clinical risk factors are assessed. Odds ratios, the proportion of positive events to negative events for a given test result, are also commonly used (odds are according to the formula p / (1-p) where p is the probability of event and (1- p) is the probability of no event) to no- conversion. "Risk evaluation," or "evaluation of risk" in the context of the present invention encompasses making a prediction of the probability, odds, or likelihood that an event or disease state may occur, the rate of occurrence of the event or conversion from one disease state to another. Risk evaluation can also comprise prediction of future clinical parameters, traditional laboratory risk factor values, or other indices of relapse, either in absolute or relative terms in reference to a previously measured population. The methods of the present invention may be used to make continuous or categorical measurements of the risk of conversion, thus diagnosing and defining the risk spectrum of a category of subjects defined as being at risk of conversion. In the categorical scenario, the invention can be used to discriminate between normal and other subject cohorts at higher risk.

[0018] In some embodiments, the subject has at least one premalignant lesion.

[0019] 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.

[0020] In some embodiments, the subject 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. bronchoscopy, colonoscopy and sigmoidoscopy), sample occult blood testing, computed tomography (CT) or other imaging procedure.

[0021] As used herein, the term “sample” to any biological sample obtained from the purpose of evaluation in vitro.

[0022] In some embodiments, the biological sample is a tissue sample. The term “tissue sample” includes sections of tissues such as biopsy or autopsy samples and frozen sections taken for histological purposes. In some embodiments, the tissue sample is obtained from the premalignant lesion. Said tissue sample is obtained for the purpose of the in vitro evaluation. In some embodiments, the tissue sample may result from a biopsy performed in the premalignant lesion of the patient. 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 recognised 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.

[0023] In particular, the non-coding RNA of the present invention encodes for a dark antigen. As used herein, the term “dark antigen” has its general meaning in the art and refers to a class of cancerspecific peptide-HLA epitopes 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.

[0024] In some embodiments, the method of the present invention comprises determining the level of one or more ncRNA(s) selected from Table A:

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[0064] In some embodiments, the method of the present invention comprises determining the level of one or more ncRNAs selected from Table B:

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[0072] In some embodiments, the method of the present invention comprises determining the level of one or more ncRNAs disclosed in Tables 2 to 25 below (without considering in these Tables those only referring to protein coding markers).

[0073] Typically, the level of a gene may be determined by determining the quantity of ncRNA. Methods for determining the quantity of ncRNA are well known in the art. For example the nucleic acid contained in the biological samples (e.g., cell or tissue prepared from the subject) is first extracted according to standard methods, for example using lytic enzymes or chemical solutions or extracted by nucleic-acid-binding resins following the manufacturer's instructions. The extracted mRNA is then detected by hybridization (e. g., Northern blot analysis, in situ hybridization) and / or amplification (e.g., RT-PCR). Other methods of Amplification include ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence based amplification (NASBA).

[0074] Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In some embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization.

[0075] Typically, the nucleic acid probes include one or more labels, for example to permit detection of a target nucleic acid molecule using the disclosed probes. In various applications, such as in situ hybridization procedures, a nucleic acid probe includes a label (e.g., a detectable label). A “detectable label” is a molecule or material that can be used to produce a detectable signal that indicates the presence or concentration of the probe (particularly the bound or hybridized probe) in a sample. Thus, a labeled nucleic acid molecule provides an indicator of the presence or concentration of a target nucleic acid sequence (e.g., genomic target nucleic acid sequence) (to which the labeled uniquely specific nucleic acid molecule is bound or hybridized) in a sample. A label associated with one or more nucleic acid molecules (such as a probe generated by the disclosed methods) can be detected either directly or indirectly. A label can be detected by any known or yet to be discovered mechanism including absorption, emission and / or scattering of a photon (including radio frequency, microwave frequency, infrared frequency, visible frequency and ultra-violet frequency photons). Detectable labels include colored, fluorescent, phosphorescent and luminescent molecules and materials, catalysts (such as enzymes) that convert one substance into another substance to provide a detectable difference (such as by converting a colorless substance into a colored substance or vice versa, or by producing a precipitate or increasing sample turbidity), haptens that can be detected by antibody binding interactions, and paramagnetic and magnetic molecules or materials. Particular examples of detectable labels include fluorescent molecules (or fluorochromes). Numerous fluorochromes are known to those of skill in the art, and can be selected, for example from Life Technologies (formerly Invitrogen), e.g., see, The Handbook — A Guide to Fluorescent Probes and Labeling Technologies). Examples of particular fluorophores that can be attached (for example, chemically conjugated) to a nucleic acid molecule (such as a uniquely specific binding region) are provided in U. S. Pat. No. 5,866, 366 to Nazarenko et al., such as 4-acetamido-4'-isothiocyanatostilbene-2,2' disulfonic acid, acridine and derivatives such as acridine and acridine isothiocyanate, 5-(2'-aminoethyl) aminonaphthalene-l-sulfonic acid (EDANS), 4-amino -N- [3 vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate (Lucifer Yellow VS), N-(4-anilino-l-naphthyl)mal eimide, anthranilamide, Brilliant Yellow, coumarin and derivatives such as coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4-trifluoromethylcoumarin (Coumarin 151); cyanosine; 4',6-diamidino-2-phenylindole (DAPI); 5',5"dibromopyrogallol-sulfonephthalein (Bromopyrogallol Red); 7 -diethylamino -3 - (4'-isothiocyanatophenyl)-4-methylcoumarin; diethylenetriamine pentaacetate; 4,4'-diisothiocyanatodihydro-stilbene-2,2'-disulfonic acid; 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid; 5-[dimethylamino] naphthalene-1-sulfonyl chloride (DNS, dansyl chloride); 4-(4'-dimethylaminophenylazo)benzoic acid (DABCYL); 4-dimethylaminophenylazophenyl-4'-isothiocyanate (DABITC); eosin and derivatives such as eosin and eosin isothiocyanate; erythrosin and derivatives such as erythrosin B and erythrosin isothiocyanate; ethidium; fluorescein and derivatives such as 5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2-yl)aminofluorescein (DTAF), 2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein (JOE), fluorescein, fluorescein isothiocyanate (FITC), and QFITC (RITC); 2',7'-difluorofluorescein (OREGON GREEN®); fluorescamine; IR144; IR1446; Malachite Green isothiocyanate; 4-methylumbelliferone; ortho cresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B -phycoerythrin; o-phthaldialdehyde; pyrene and derivatives such as pyrene, pyrene butyrate and succinimidyl 1 -pyrene butyrate; Reactive Red 4 (Cibacron Brilliant Red 3B-A); rhodamine and derivatives such as 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride, rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, rhodamine green, sulforhodamine B, sulforhodamine 101 and sulfonyl chloride derivative of sulforhodamine 101 (Texas Red); N, N, N', N'-tetramethyl-6-carboxyrhodamine (TAMRA); tetramethyl rhodamine; tetramethyl rhodamine isothiocyanate (TRITC); riboflavin; rosolic acid and terbium chelate derivatives. Other suitable fluorophores include thiol-reactive europium chelates which emit at approximately 617 mn (Heyduk and Heyduk, Analyt. Biochem. 248:216-27, 1997; J. Biol. Chem. 274:3315-22, 1999), as well as GFP, LissamineTM, diethylaminocoumarin, fluorescein chlorotriazinyl, naphthofluorescein, 4, 7-di chlororhodamine and xanthene (as described in U. S. Pat. No. 5,800,996 to Lee et al.) and derivatives thereof. Other fluorophores known to those skilled in the art can also be used, for example those available from Life Technologies (Invitrogen; Molecular Probes (Eugene, Oreg.)) and including the ALEXA FLUOR® series of dyes (for example, as described in U. S. Pat. Nos. 5,696,157, 6, 130, 101 and 6,716,979), the BODIPY series of dyes (dipyrromethene boron difluoride dyes, for example as described in U. S. Pat. Nos. 4,774,339, 5,187,288, 5,248,782, 5,274,113, 5,338,854, 5,451,663 and 5,433,896), Cascade Blue (an amine reactive derivative of the sulfonated pyrene described in U. S. Pat. No.

[0076] 5,132,432) and Marina Blue (U. S. Pat. No. 5,830,912).

[0077] In addition to the fluorochromes described above, a fluorescent label can be a fluorescent nanoparticle, such as a semiconductor nanocrystal, e.g., a QUANTUM DOTTM (obtained, for example, from Life Technologies (QuantumDot Corp, Invitrogen Nanocrystal Technologies, Eugene, Oreg.); see also, U. S. Pat. Nos. 6,815,064; 6,682,596; and 6,649, 138). Semiconductor nanocrystals are microscopic particles having size-dependent optical and / or electrical properties. When semiconductor nanocrystals are illuminated with a primary energy source, a secondary emission of energy occurs of a frequency that corresponds to the handgap of the semiconductor material used in the semiconductor nanocrystal. This emission can he detected as colored light of a specific wavelength or fluorescence. Semiconductor nanocrystals with different spectral characteristics are described in e.g., U. S. Pat. No. 6,602,671. Semiconductor nanocrystals that can he coupled to a variety of biological molecules (including dNTPs and / or nucleic acids) or substrates by techniques described in, for example, Bruchez et al., Science 281:2013-2016, 1998; Chan et al., Science 281:2016-2018, 1998; and U. S. Pat. No. 6,274,323. Formation of semiconductor nanocrystals of various compositions are disclosed in, e.g., U. S. Pat. Nos. 6,927, 069; 6,914,256; 6,855,202; 6,709,929; 6,689,338; 6,500,622; 6,306,736; 6,225,198; 6,207,392; 6,114,038; 6,048,616; 5,990,479; 5,690,807; 5,571,018; 5,505,928; 5,262,357 and in U. S. Patent Publication No. 2003 / 0165951 as well as PCT Publication No.

[0078] 99 / 26299 (published May 27, 1999). Separate populations of semiconductor nanocrystals can he produced that are identifiable based on their different spectral characteristics. For example, semiconductor nanocrystals can he produced that emit light of different colors based on their composition, size or size and composition. For example, quantum dots that emit light at different wavelengths based on size (565 mn, 655 mn, 705 mn, or 800 mn emission wavelengths), which are suitable as fluorescent labels in the probes disclosed herein are available from Life Technologies (Carlshad, Calif.).

[0079] Additional labels include, for example, radioisotopes (such as3H), metal chelates such as DOTA and DPTA chelates of radioactive or paramagnetic metal ions like Gd3+, and liposomes. Detectable labels that can he used with nucleic acid molecules also include enzymes, for example horseradish peroxidase, alkaline phosphatase, acid phosphatase, glucose oxidase, betagalactosidase, beta-glucuronidase, or beta-lactamase. Alternatively, an enzyme can he used in a metallographic detection scheme. For example, silver in situ hybridization (SISH) procedures involve metallographic detection schemes for identification and localization of a hybridized genomic target nucleic acid sequence. Metallographic detection methods include using an enzyme, such as alkaline phosphatase, in combination with a water-soluble metal ion and a redox-inactive substrate of the enzyme. The substrate is converted to a redox-active agent by the enzyme, and the redoxactive agent reduces the metal ion, causing it to form a detectable precipitate. (See, for example, U. S. Patent Application Publication No. 2005 / 0100976, PCT Publication No. 2005 / 003777 and U. S. Patent Application Publication No. 2004 / 0265922). Metallographic detection methods also include using an oxido-reductase enzyme (such as horseradish peroxidase) along with a water soluble metal ion, an oxidizing agent and a reducing agent, again to form a detectable precipitate. (See, for example, U. S. Pat. No. 6,670,113).

[0080] Probes made using the disclosed methods can be used for nucleic acid detection, such as ISH procedures (for example, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver in situ hybridization (SISH)) or comparative genomic hybridization (CGH).

[0081] In situ hybridization (ISH) involves contacting a sample containing target nucleic acid sequence (e.g., genomic target nucleic acid sequence) in the context of a metaphase or interphase chromosome preparation (such as a cell or tissue sample mounted on a slide) with a labeled probe specifically hybridizable or specific for the target nucleic acid sequence (e.g., genomic target nucleic acid sequence). The slides are optionally pretreated, e.g., to remove paraffin or other materials that can interfere with uniform hybridization. The sample and the probe are both treated, for example by heating to denature the double stranded nucleic acids. The probe (formulated in a suitable hybridization buffer) and the sample are combined, under conditions and for sufficient time to permit hybridization to occur (typically to reach equilibrium). The chromosome preparation is washed to remove excess probe, and detection of specific labeling of the chromosome target is performed using standard techniques.

[0082] For example, a biotinylated probe can be detected using fluorescein-labeled avidin or avidinalkaline phosphatase. For fluorochrome detection, the fluorochrome can be detected directly, or the samples can be incubated, for example, with fluorescein isothiocyanate (FITC)-conjugated avidin. Amplification of the FITC signal can be effected, if necessary, by incubation with biotin-conjugated goat antiavidin antibodies, washing and a second incubation with FITC-conjugated avidin. For detection by enzyme activity, samples can be incubated, for example, with streptavidin, washed, incubated with biotin-conjugated alkaline phosphatase, washed again and pre-equilibrated (e.g., in alkaline phosphatase (AP) buffer). For a general description of in situ hybridization procedures, see, e.g., U. S. Pat. No. 4,888,278.

[0083] Numerous procedures for FISH, CISH, and SISH are known in the art. For example, procedures for performing FISH are described in U. S. Pat. Nos. 5,447,841; 5,472,842; and 5,427,932; and for example, in Pirlkel et al., Proc. Natl. Acad. Sci. 83:2934-2938, 1986; Pinkel et al., Proc. Natl. Acad. Sci. 85:9138-9142, 1988; and Lichter et al., Proc. Natl. Acad. Sci. 85:9664-9668, 1988. CISH is described in, e.g., Tanner et al., Am..1. Pathol. 157:1467-1472, 2000 and U. S. Pat. No. 6,942,970. Additional detection methods are provided in U. S. Pat. No. 6,280,929.

[0084] Numerous reagents and detection schemes can be employed in conjunction with FISH, CISH, and SISH procedures to improve sensitivity, resolution, or other desirable properties. As discussed above probes labeled with fluorophores (including fluorescent dyes and QUANTUM DOTS®) can be directly optically detected when performing FISH. Alternatively, the probe can be labeled with a nonfluorescent molecule, such as a hapten (such as the following nonlimiting examples: biotin, digoxigenin, DNP, and various oxazoles, pyrrazoles, thiazoles, nitroaryls, benzofurazans, triterpenes, ureas, thioureas, rotenones, coumarin, courmarin-based compounds, Podophyllotoxin, Podophyllotoxin-based compounds, and combinations thereof), ligand or other indirectly detectable moiety. Probes labeled with such non-fluorescent molecules (and the target nucleic acid sequences to which they bind) can then be detected by contacting the sample (e.g., the cell or tissue sample to which the probe is bound) with a labeled detection reagent, such as an antibody (or receptor, or other specific binding partner) specific for the chosen hapten or ligand. The detection reagent can be labeled with a fluorophore (e.g., QUANTUM DOT®) or with another indirectly detectable moiety, or can be contacted with one or more additional specific binding agents (e.g., secondary or specific antibodies), which can be labeled with a fluorophore.

[0085] In other examples, the probe, or specific binding agent (such as an antibody, e.g., a primary antibody, receptor or other binding agent) is labeled with an enzyme that is capable of converting a fluorogenic or chromogenic composition into a detectable fluorescent, colored or otherwise detectable signal (e.g., as in deposition of detectable metal particles in SISH). As indicated above, the enzyme can be attached directly or indirectly via a linker to the relevant probe or detection reagent. Examples of suitable reagents (e.g., binding reagents) and chemistries (e.g., linker and attachment chemistries) are described in U. S. Patent Application Publication Nos. 2006 / 0246524; 2006 / 0246523, and 2007 / 01 17153.

[0086] It will he appreciated by those of skill in the art that by appropriately selecting labelled probespecific binding agent pairs, multiplex detection schemes can he produced to facilitate detection of multiple target nucleic acid sequences (e.g., genomic target nucleic acid sequences) in a single assay (e.g., on a single cell or tissue sample or on more than one cell or tissue sample). For example, a first probe that corresponds to a first target sequence can he labelled with a first hapten, such as biotin, while a second probe that corresponds to a second target sequence can be labelled with a second hapten, such as DNP. Following exposure of the sample to the probes, the bound probes can he detected by contacting the sample with a first specific binding agent (in this case avidin labelled with a first fluorophore, for example, a first spectrally distinct QUANTUM DOT®, e.g., that emits at 585 mn) and a second specific binding agent (in this case an anti-DNP antibody, or antibody fragment, labelled with a second fluorophore (for example, a second spectrally distinct QUANTUM DOT®, e.g., that emits at 705 mn). Additional probes / binding agent pairs can he added to the multiplex detection scheme using other spectrally distinct fluorophores. Numerous variations of direct, and indirect (one step, two step or more) can he envisioned, all of which are suitable in the context of the disclosed probes and assays.

[0087] Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500. Primers typically are shorter single-stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified. The probes and primers are “specific” to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC. SCC is a 0.15 MNaCl, 0.015 M Na-citrate).

[0088] The nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit. Such a kit includes consensus primers and molecular probes. A preferred kit also includes the components necessary to determine if amplification has occurred. The kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.

[0089] In some embodiments, the methods of the invention comprise the steps of providing total RNAs extracted from cells and subjecting the RNAs to amplification and hybridization to specific probes, more particularly by means of a quantitative or semi-quantitative RT-PCR.

[0090] In some embodiments, the level is determined by DNA chip analysis. Such DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere-sized bead. A microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose. Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs. To determine the level, a sample from a test subject, optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface. The labelled hybridized complexes are then detected and can be quantified or semi -quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling. Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200-210).

[0091] In some embodiments, the nCounter® Analysis system is used to detect intrinsic gene expression. The basis of the nCounter® Analysis system is the unique code assigned to each nucleic acid target to be assayed (International Patent Application Publication No. WO 08 / 124847, U. S. Patent No. 8,415,102 and Geiss et al. Nature Biotechnology. 2008. 26(3): 317-325; the contents of which are each incorporated herein by reference in their entireties). The code is composed of an ordered series of colored fluorescent spots which create a unique barcode for each target to be assayed. A pair of probes is designed for each DNA or RNA target, a biotinylated capture probe and a reporter probe carrying the fluorescent barcode. This system is also referred to, herein, as the nanoreporter code system. Specific reporter and capture probes are synthesized for each target. The reporter probe can comprise at a least a first label attachment region to which are attached one or more label monomers that emit light constituting a first signal; at least a second label attachment region, which is non-over-lapping with the first label attachment region, to which are attached one or more label monomers that emit light constituting a second signal; and a first target- specific sequence. Preferably, each sequence specific reporter probe comprises a target specific sequence capable of hybridizing to no more than one gene and optionally comprises at least three, or at least four label attachment regions, said attachment regions comprising one or more label monomers that emit light, constituting at least a third signal, or at least a fourth signal, respectively. The capture probe can comprise a second target-specific sequence; and a first affinity tag. In some embodiments, the capture probe can also comprise one or more label attachment regions. Preferably, the first targetspecific sequence of the reporter probe and the second target- specific sequence of the capture probe hybridize to different regions of the same gene to be detected. Reporter and capture probes are all pooled into a single hybridization mixture, the "probe library". The relative abundance of each target is measured in a single multiplexed hybridization reaction. The method comprises contacting the tissue sample with a probe library, such that the presence of the target in the biological sample creates a probe pair - target complex. The complex is then purified. More specifically, the sample is combined with the probe library, and hybridization occurs in solution. After hybridization, the tripartite hybridized complexes (probe pairs and target) are purified in a two-step procedure using magnetic beads linked to oligonucleotides complementary to universal sequences present on the capture and reporter probes. This dual purification process allows the hybridization reaction to be driven to completion with a large excess of target-specific probes, as they are ultimately removed, and, thus, do not interfere with binding and imaging of the sample. All post hybridization steps are handled robotically on a custom liquid-handling robot (Prep Station, NanoString Technologies). Purified reactions are typically deposited by the Prep Station into individual flow cells of a sample cartridge, bound to a streptavidin-coated surface via the capture probe, electrophoresed to elongate the reporter probes, and immobilized. After processing, the sample cartridge is transferred to a fully automated imaging and data collection device (Digital Analyzer, NanoString Technologies). The level of a target is measured by imaging each sample and counting the number of times the code for that target is detected. For each sample, typically 600 fields-of-view (FOV) are imaged (1376 X 1024 pixels) representing approximately 10 mm2of the binding surface. Typical imaging density is 100- 1200 counted reporters per field of view depending on the degree of multiplexing, the amount of sample input, and overall target abundance. Data is output in simple spreadsheet format listing the number of counts per target, per sample. This system can be used along with nanoreporters. Additional disclosure regarding nanoreporters can be found in International Publication No. WO 07 / 076129 and W007 / 076132, and US Patent Publication No. 2010 / 0015607 and 2010 / 0261026, the contents of which are incorporated herein in their entireties. Further, the term nucleic acid probes and nanoreporters can include the rationally designed (e.g. synthetic sequences) described in International Publication No. WO 2010 / 019826 and US Patent Publication No.2010 / 0047924, incorporated herein by reference in its entirety.

[0092] Level of a gene may be expressed as absolute level or normalized level. Typically, levels are normalized by correcting the absolute level of a gene by comparing its expression to the expression of a gene that is not a relevant for determining the risk. This normalization allows the comparison of the level in one sample, e.g., a subject sample, to another sample, or between samples from different sources.

[0093] In some embodiments, the method of the present invention further comprises comparing the expression level of the ncRNA with a predetermined reference value wherein detecting a difference between the expression level of the ncRNA and the predetermined reference value indicates whether the subject is or is not at risk of having cancer.

[0094] In some embodiments, the predetermined reference value is a relative to a number or value derived from population studies, including without limitation, subjects of the same or similar age range, subjects in the same or similar ethnic group, and subjects having the same severity of premalignant lesion. Such predetermined reference values can be derived from statistical analyses and / or risk prediction data of populations obtained from mathematical algorithms and computed indices. In some embodiments, retrospective measurement of the level of the ncRNA in properly banked historical subject samples may be used in establishing these predetermined reference values. Accordingly, in some embodiments, the predetermined reference value is a threshold value or a cut-off value. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit / risk balance (clinical consequences of false positive and false negative). Typically, the optimal sensitivity and specificity (and so the threshold value) can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data. For example, after determining the level of the ncRNA in a group of reference, one can use algorithmic analysis for the statistic treatment of the measured levels of the ncRNA in samples to be tested, and thus obtain a classification standard having significance for sample classification. The full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests. ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1-specificity). It reveals the relationship between sensitivity and specificity with the image composition method. A series of different cut-off values (thresholds or critical values, boundary values between normal and abnormal results of diagnostic test) are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis. On the ROC curve, the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values. The AUC value of the ROC curve is between 1.0 and 0.5. When AUC>0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate. When AUC is higher than 0.9, the accuracy is quite high. This algorithmic method is preferably done with a computer. Existing software or systems in the art may be used for the drawing of the ROC curve, such as: MedCalc 9.2.0.1 medical statistical software, SPSS 9.0, ROCPOWER. SAS, DESIGNROC. FOR, MULTIREADER POWER. SAS, CREATE-ROC. SAS, GB STAT VIO. O (Dynamic Microsystems, Inc. Silver Spring, Md., USA), etc.

[0095] Typically, a high level of the ncRNA indicates that the subject is at low risk of having a cancer. Conversely, a low level of the ncRNA indicates that the subject is at high risk of having a cancer.

[0096] As used herein, the term “high” refers to a measure that is greater than normal, greater than a standard such as a predetermined reference value or a subgroup measure or that is relatively greater than another subgroup measure. For example, high levels of the ncRNA refers to a level of the ncRNA that is greater than a normal the ncRNA level. A normal the ncRNA level may be determined according to any method available to one skilled in the art. High level of the ncRNA may also refer to a level that is equal to or greater than a predetermined reference value, such as a predetermined cutoff. High level of the ncRNA may also refer to a level of the ncRNA wherein a high the ncRNA subgroup has relatively greater levels of the ncRNA than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a subgroup whose measure is high (i.e., higher than the median) and another subgroup whose measure is low. In some cases, a “high” level may comprise a range of level that is very high and a range of level that is “moderately high” where moderately high is a level that is greater than normal, but less than “very high”.

[0097] As used herein, the term “low” refers to a level that is less than normal, less than a standard such as a predetermined reference value or a subgroup measure that is relatively less than another subgroup level. For example, low level of the ncRNA means a level of the ncRNA that is less than a normal level of in a particular set of samples of patients. A normal level of the ncRNA measure may be determined according to any method available to one skilled in the art. Low level of the ncRNA may also mean a level that is less than a predetermined reference value, such as a predetermined cutoff. Low level of the ncRNA may also mean a level wherein a low level the ncRNA subgroup is relatively lower than another subgroup. For example, without limitation, according to the present specification, two distinct patient subgroups can be created by dividing samples around a mathematically determined point, such as, without limitation, a median, thus creating a group whose measure is low (i.e., less than the median) with respect to another group whose measure is high (i.e., greater than the median).

[0098] In some embodiments, the method of the present invention further comprises a step of determining the expression level of one or more additional immune markers in the biological sample obtained from the subject.

[0099] As used herein, the term “immune marker” consists of any detectable, measurable or quantifiable parameter that is indicative of the status of the immune response of the subject. In some embodiments, the immune marker includes the presence of, or the number or density of, cells from the immune system. In some embodiments, the immune marker includes the presence of, or the amount of proteins specifically produced by cells from the immune system. In some embodiments, the immune marker includes the presence of, or the amount of, any biological material that is indicative of the level of genes related to the raising of a specific immune response of the host. Thus, in some embodiments, the immune marker includes the presence of, or the amount of, messenger RNA (mRNA) transcribed from genomic DNA encoding proteins which are specifically produced by cells from the immune system. In some embodiments, the immune marker includes surface antigens that are specifically expressed by cells from the immune system, including by B lymphocytes, T lymphocytes, monocytes / macrophages dendritic cells, NK cells, NKT cells, and NK-DC cells or alternatively mRNA encoding for said surface antigens.

[0100] In some embodiments, the presence of main adaptive immune cell types in the biological sample is determined using 6-marker multiplex immunofluorescence: 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+). In some embodiments, the functional status of T cells in the biological sample is determined using 8 marker multiplex IHC including T cells markers (CD3 and CD8), exhaustion markers (TIM3, PD1, PDL1, TCF1) and one proliferation marker (Ki67) in addition to cytokeratin. In some embodiments, the presence of tertiary lymphoid structures ( TLS ”) in the biological sample is determined using CD3 and CD20 staining as described in the EXAMPLE. In some embodiments, the relative abundance and / or maturation of TLS is determined in the biological sample by determining the expression level of CD3, CD20, CD 19, CXCR5, CD4, CD8, CD21, CD23, PD1, and Ki67. In some embodiments, the method of the present invention further comprises determining the expression levels of PDL1, CD3, CD20, CD19, CXCR5, CD4, CD8, PD1, Ki67, and TIM3. In some embodiments, the method of the present invention further comprises determining the expression levels of CD3 and CD 8.

[0101] In some embodiments, a score which is a composite of the expression levels of the different ncRNAs and optionally of one or more immune markers is determined and compared to the predetermined reference value wherein a difference between said score and said predetermined reference value is indicative whether the subject is at risk of having cancer.

[0102] In some embodiments, the method of the invention comprises the use of a classification algorithm typically selected from Linear Discriminant Analysis (LDA), Topological Data Analysis (TDA), Neural Networks, Support Vector Machine (SVM) algorithm and Random Forests algorithm (RF) such as described in the Example. In some embodiments, the method of the invention comprises the step of determining the subject response using a classification algorithm. As used herein, the term "classification algorithm" has its general meaning in the art and refers to classification and regression tree methods and multivariate classification well known in the art such as described in US 8,126,690; WO2008 / 156617. As used herein, the term “support vector machine (SVM)” is a universal learning machine useful for pattern recognition, whose decision surface is parameterized by a set of support vectors and a set of corresponding weights, refers to a method of not separately processing, but simultaneously processing a plurality of variables. Thus, the support vector machine is useful as a statistical tool for classification. The support vector machine non-linearly maps its n-dimensional input space into a high dimensional feature space, and presents an optimal interface (optimal parting plane) between features. The support vector machine comprises two phases: a training phase and a testing phase. In the training phase, support vectors are produced, while estimation is performed according to a specific rule in the testing phase. In general, SVMs provide a model for use in classifying each of n subjects to two or more disease categories based on one k-dimensional vector (called a k-tuple) of biomarker measurements per subject. An SVM first transforms the k-tuples using a kernel function into a space of equal or higher dimension. The kernel function projects the data into a space where the categories can be better separated using hyperplanes than would be possible in the original data space. To determine the hyperplanes with which to discriminate between categories, a set of support vectors, which lie closest to the boundary between the disease categories, may be chosen. A hyperplane is then selected by known SVM techniques such that the distance between the support vectors and the hyperplane is maximal within the bounds of a cost function that penalizes incorrect predictions. This hyperplane is the one which optimally separates the data in terms of prediction (Vapnik, 1998 Statistical Learning Theory. New York: Wiley). Any new observation is then classified as belonging to any one of the categories of interest, based where the observation lies in relation to the hyperplane. When more than two categories are considered, the process is carried out pairwise for all of the categories and those results combined to create a rule to discriminate between all the categories. As used herein, the term "Random Forests algorithm" or "RF" has its general meaning in the art and refers to classification algorithm such as described in US 8,126,690; WO2008 / 156617. Random Forest is a decision-tree-based classifier that is constructed using an algorithm originally developed by Leo Breiman (Breiman L, "Random forests," Machine Learning 2001, 45:5-32). The classifier uses a large number of individual decision trees and decides the class by choosing the mode of the classes as determined by the individual trees. The individual trees are constructed using the following algorithm: (1) Assume that the number of cases in the training set is N, and that the number of variables in the classifier is M; (2) Select the number of input variables that will be used to determine the decision at a node of the tree; this number, m should be much less than M; (3) Choose a training set by choosing N samples from the training set with replacement; (4) For each node of the tree randomly select m of the M variables on which to base the decision at that node; (5) Calculate the best split based on these m variables in the training set. In some embodiments, the score is generated by a computer program.

[0103] In some embodiments, the method of the present invention comprises a) quantifying the level of a plurality of ncRNAs and optionally one or more immune marker(s) in the biological sample; b) implementing an algorithm on data comprising the quantified plurality of ncRNAs and immune markers so as to obtain an algorithm output; c) determining the probability that the subject will develop a cancer from the algorithm output of step b).

[0104] The algorithm of the present invention can be performed by one or more programmable processors executing one or more computer programs to perform functions by operating on input data and generating output. The algorithm can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit). Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a processor for performing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. However, a computer need not have such devices. Moreover, a computer can be embedded in another device. Computer-readable media suitable for storing computer program instructions and data include all forms of non-volatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices; magnetic disks, e.g., internal hard disks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry. To provide for interaction with a user, embodiments of the invention can be implemented on a computer having a display device, e.g., in non-limiting examples, a CRT (cathode ray tube) or LCD (liquid crystal display) monitor, for displaying information to the user and a keyboard and a pointing device, e.g., a mouse or a trackball, by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback, e.g., visual feedback, auditory feedback, or tactile feedback; and input from the user can be received in any form, including acoustic, speech, or tactile input. Accordingly, in some embodiments, the algorithm can be implemented in a computing system that includes a back-end component, e.g., as a data server, or that includes a middleware component, e.g., an application server, or that includes a front-end component, e.g., a client computer having a graphical user interface or a Web browser through which a user can interact with an implementation of the invention, or any combination of one or more such back-end, middleware, or front-end components. The components of the system can be interconnected by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include a local area network (“LAN”) and a wide area network (“WAN”), e.g., the Internet. The computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.

[0105] A further object of the present invention relates to a method for the prophylactic treatment of cancer in a subject having at least one premalignant lesion comprising administering to the subject a therapeutically effective amount of at least one chemopreventive agent.

[0106] 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.

[0107] In some embodiments, the subject has been considered as being at risk of having cancer by the predictive method of the present invention. In some embodiments, the chemopreventive agent is selected from the group consisting of alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophy cin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0108] In some embodiments, the chemopreventive agent is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" has its general meaning in the art and refers to any compound inhibiting the function of an immune inhibitory checkpoint protein. Inhibition includes reduction of function and full blockade. Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. A number of immune checkpoint inhibitors are known and in analogy of these known immune checkpoint protein inhibitors, alternative immune checkpoint inhibitors may be developed in the (near) future. The immune checkpoint inhibitors include peptides, antibodies, nucleic acid molecules and small molecules. Examples of immune checkpoint inhibitor includes PD-1 antagonist, PD-L1 antagonist, PD-L2 antagonist CTLA-4 antagonist, VISTA antagonist, TIM-3 antagonist, LAG-3 antagonist, GITR antagonist, IDO antagonist, KIR2D antagonist, A2AR antagonist, B7-H3 antagonist, B7-H4 antagonist, and BTLA antagonist.

[0109] In some embodiments, PD-1 (Programmed Death-1) axis antagonists include PD-1 antagonist (for example anti-PD-1 antibody), PD-L1 (Programmed Death Ligand-1) antagonist (for example anti-PD-Ll antibody) and PD-L2 (Programmed Death Ligand-2) antagonist (for example anti-PD-L2 antibody). In some embodiments, the anti-PD-1 antibody is selected from the group consisting of MDX-1106 (also known as Nivolumab, MDX-1106-04, ONO-4538, BMS-936558, and Opdivo®), Merck 3475 (also known as Pembrolizumab, MK-3475, Lambrolizumab, Keytruda®, and SCH-900475), and CT-011 (also known as Pidilizumab, hBAT, and hBAT-1). In some embodiments, the PD-1 binding antagonist is AMP-224 (also known as B7-DCIg). In some embodiments, the anti-PD-Ll antibody is selected from the group consisting of YW243.55. S70, MPDL3280A, MDX-1105, and MEDI4736. MDX-1105, also known as BMS-936559, is an anti-PD-Ll antibody described in W02007 / 005874. Antibody YW243.55. S70 is an anti-PD-Ll described in WO 2010 / 077634 AL MEDI4736 is an anti-PD-Ll antibody described in WO2011 / 066389 and US2013 / 034559. MDX-1106, also known as MDX-1106-04, ONO-4538 or BMS-936558, is an anti-PD-1 antibody described in U. S. Pat. No. 8,008,449 and W02006 / 121168. Merck 3745, also known as MK-3475 or SCH-900475, is an anti-PD-1 antibody described in U. S. Pat. No. 8,345,509 and W02009 / 114335. CT-011 (Pidizilumab), also known as hBAT or hBAT-1, is an anti-PD-1 antibody described in W02009 / 101611. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in W02010 / 027827 and WO2011 / 066342. Atezolimumab is an anti-PD-Ll antibody described in U. S. Pat. No. 8,217,149. Avelumab is an anti-PD-Ll antibody described in US 20140341917. CA-170 is a PD-1 antagonist described in W02015033301 & WO2015033299. Other anti-PD-1 antibodies are disclosed in U. S. Pat. No. 8,609,089, US 2010028330, and / or US 20120114649. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab or Pidilizumab. In some embodiments, PD-L1 antagonist is selected from the group comprising of Avelumab, BMS-936559, CA-170, Durvalumab, MCLA-145, SP142, STI-A1011, STIA1012, STI-A1010, STI-A1014, Al 10, KY1003 and Atezolimumab and the preferred one is Avelumab, Durvalumab or Atezolimumab. Other molecules with similar mechanisms that would be developed in the future are also potential candidate for cancer chemoprevention.

[0110] In some embodiments, CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4) antagonists are selected from the group consisting of anti-CTLA-4 antibodies, human anti-CTLA-4 antibodies, mouse anti-CTLA-4 antibodies, mammalian anti-CTLA-4 antibodies, humanized anti-CTLA-4 antibodies, monoclonal anti-CTLA-4 antibodies, polyclonal anti-CTLA-4 antibodies, chimeric anti-CTLA-4 antibodies, MDX-010 (Ipilimumab), Tremelimumab, anti-CD28 antibodies, anti-CTLA-4 adnectins, anti-CTLA-4 domain antibodies, single chain anti-CTLA-4 fragments, heavy chain anti-CTLA-4 fragments, light chain anti-CTLA-4 fragments, inhibitors of CTLA-4 that agonize the co-stimulatory pathway, the antibodies disclosed in PCT Publication No. WO 2001 / 014424, the antibodies disclosed in PCT Publication No. WO 2004 / 035607, the antibodies disclosed in U. S. Publication No. 2005 / 0201994, and the antibodies disclosed in granted European Patent No. EP 1212422 B. Additional CTLA-4 antibodies are described in U. S. Pat. Nos. 5,811,097; 5,855,887; 6,051,227; and 6,984,720; in PCT Publication Nos. WO 01 / 14424 and WO 00 / 37504; and in U. S. Publication Nos. 2002 / 0039581 and 2002 / 086014. Other anti-CTLA-4 antibodies that can be used in a method of the present invention include, for example, those disclosed in: WO 98 / 42752; U. S. Pat. Nos. 6,682,736 and 6,207,156; Hurwitz et al., Proc. Natl. Acad. Sci. USA, 95(17): 10067-10071 (1998); Camacho et al., J. Clin: Oncology, 22(145): Abstract No. 2505 (2004) (antibody CP-675206); Mokyr et al., Cancer Res., 58:5301-5304 (1998), and U. S. Pat. Nos. 5,977,318, 6,682,736, 7,109,003, and 7,132,281. A preferred clinical CTLA-4 antibody is human monoclonal antibody (also referred to as MDX-010 and Ipilimumab with CAS No. 477202-00-9 and available from Medarex, Inc., Bloomsbury, N. J.) is disclosed in WO 01 / 14424. With regard to CTLA-4 antagonist (antibodies), these are known and include Tremelimumab (CP-675,206) and Ipilimumab. Other molecules with similar mechanisms that would be developed in the future are also potential candidate for cancer chemoprevention.

[0111] Other immune-checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-4211). Other immune-checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors. In particular, the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834). Also included are TIM-3 (T-cell immunoglobulin domain and mucin domain 3) inhibitors (Fourcade et al., 2010, J. Exp. Med. 207:2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207:2187-94). As used herein, the term “TIM-3” has its general meaning in the art and refers to T cell immunoglobulin and mucin domain-containing molecule 3. The natural ligand of TIM-3 is galectin 9 (Gal9). Accordingly, the term “TIM-3 inhibitor” as used herein refers to a compound, substance or composition that can inhibit the function of TIM-3. For example, the inhibitor can inhibit the expression or activity of TIM-3, modulate or block the TIM-3 signaling pathway and / or block the binding of TIM-3 to galectin-9. Antibodies having specificity for TIM-3 are well known in the art and typically those described in WO2011155607, W02013006490 and WO2010117057. Other molecules with similar mechanisms that would be developed in the future are also potential candidate for cancer chemoprevention.

[0112] In some embodiments, the immune checkpoint inhibitor is an IDO inhibitor. Examples of IDO inhibitors are described in WO 2014150677. Examples of IDO inhibitors include without limitation 1-methyl-tryptophan (IMT), P- (3-benzofuranyl)-alanine, P-(3-benzo(b)thienyl)-alanine), 6-nitro-tryptophan, 6- fluoro-tryptophan, 4-methyl-tryptophan, 5 -methyl tryptophan, 6-methyl-tryptophan, 5 -methoxy -tryptophan, 5 -hydroxy-tryptophan, indole 3-carbinol, 3,3'-diindolylmethane, epigallocatechin gallate, 5-Br-4-Cl-indoxyl 1,3 -diacetate, 9- vinylcarbazole, acemetacin, 5 -bromo-tryptophan, 5 -bromoindoxyl diacetate, 3- Amino-naphtoic acid, pyrrolidine dithiocarbamate, 4-phenylimidazole a brassinin derivative, a thiohydantoin derivative, a P-carboline derivative or a brassilexin derivative. Preferably the IDO inhibitor is selected from 1-methyl-tryptophan, P-(3- benzofuranyl)-alanine, 6-nitro-L-tryptophan, 3-Amino-naphtoic acid and P-[3- benzo(b)thienyl] -alanine or a derivative or prodrug thereof. Other molecules with similar mechanisms that would be developed in the future are also potential candidate for cancer chemoprevention.

[0113] In some embodiments, the chemopreventive agents is a vaccine against an immune checkpoint inhibitor or a suppressive cytokine or suppressive protein. Preferred immune checkpoint inhibitors are vaccine against these molecules that specifically generate an adaptive immune response (T-cell response and B-cell response) inducing or expanding T-cells and B-cells having specificities against these immune checkpoint inhibitor or suppressive cytokine or suppressive protein. Examples of vaccine against immune checkpoint inhibitor includes proteins or peptides of PD-1, PD-L1, PD-L2 CTLA-4, VISTA, TIM-3, LAG-3, GITR, IDO, KIR2D, A2AR, B7-H3, B7-H4, and BTLA.

[0114] In some embodiments, the chemopreventive agent is administered locally in the premalignant lesion or by systemic approaches to the subject. When possible, the agent is administered via a local route. Typically, when the subject suffers from a premalignant lesion of the skin, the chemopreventive agent is topically administered to the subject. Even though systemic route is more at risk of sides effects including auto-immune responses, it is required in many cases of sites that are not accessible by local route or in case of field of cancerization.

[0115] 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.

[0116] FIGURES:

[0117] Figure 1: Transcriptomic characterization of colorectal premalignant lesions. 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.

[0118] 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 t-test. b.

[0119] 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 t-test. 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 t-test. e. Pie charts representing Distribution of ncHigh and ncLow samples across frequency groups. Fisher’s exact test.

[0120] Figure 3: Immune profiles and precancerous lesion development rate.

[0121] 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).

[0122] Figure 4: Immune profiles and polyp development rate 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.

[0123] Figure 5: ncRNA, CD8 infiltration and frequency groups

[0124] 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.

[0125] 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.

[0126] EXAMPLE:

[0127] Example 1

[0128] Methods:

[0129] Public data

[0130] 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 / ).

[0131] Clinical cohort constitution

[0132] 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 1, 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 IHC 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).

[0133] Table 1: Patients characteristics:

[0134]

[0135] Cohort annotation

[0136] 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.

[0137] Frequency group

[0138] 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).

[0139] RNA and DNA extraction

[0140] 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).

[0141] RNA sequencing and alignment

[0142] 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 2.6.1d. 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.

[0143] Differential expression analysis

[0144] Transcript wise differential expression analysis was performed using the R package DESeq2.

[0145] CMS classification

[0146] 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".

[0147] ConsensusTME scoring

[0148] 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.

[0149] Immunoediting score

[0150] 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 biological sample i, the expected number of non-synonymous Npred,i and immunogenic mutations Bpred,i were calculated as:

[0151]

[0152] The immunoediting score represented the ratio of expected to observed immunogenic mutations per non-silent mutation.

[0153] Immunogenicity estimation

[0154] 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.

[0155] T cell and B cell repertoire

[0156] 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.

[0157] Clonality scores calculation

[0158] 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:

[0159] Shannon Entropy: H(x)= -XP(x)log2 [P(x)]

[0160] For a sequence x, P(x) = sequence count / total count

[0161] 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)

[0162] where S is the number of unique TCR / CDR3 sequences.

[0163] Clonality is calculated as the inverse of the normalized entropy calculation:

[0164] Clonality score = 1 - J

[0165] The sequence count is equal to the unique number of found TCR clones per sample.

[0166] The total count is equal to the total number of found TCR clones per sample. Samples were split between low and high clonality score using a threshold based on clonality score distribution across samples.

[0167] Whole exome sequencing and alignment

[0168] 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.

[0169] Oncoplot generation

[0170] Oncoplot and total mutation burden data were generated from the MAF file using the R package maftools45.

[0171] Immunohistochemistry slide preprocessing

[0172] 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.

[0173] Multiplex Immunofluorescence

[0174] Staining

[0175] 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).

[0176] Image acquisition Stained slides were digitised with the 20X lens of the PhenoImager HT (0.5 µm / 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).

[0177] Image analysis

[0178] 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.

[0179] Multiplex Immunohistochemistry

[0180] Staining

[0181] 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 µm / 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.

[0182] Image analysis

[0183] 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.

[0184] Visualization and Statistical analysis

[0185] 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.

[0186] Results:

[0187] Polyp development rate and colorectal premalignant pathways

[0188] 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).

[0189] 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.

[0190] 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).

[0191] 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).

[0192] Mutational analysis

[0193] 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 = 1.024x10-10). 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).

[0194] Transcriptomic profiles

[0195] 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).

[0196] 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.

[0197] Differential transcript expression analysis

[0198] 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 F1 versus 29.7% of upregulated transcripts in F2 / F3 (data not shown). 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)

[0199] 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).

[0200] 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.

[0201] ncRNA and immune microenvironment

[0202] 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. 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 1 O’6) (Figure 2a).

[0203] 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).

[0204] 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 = 9.30x10-5, 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).

[0205] 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).

[0206] 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).

[0207] Polyp development rate and immune microenvironment

[0208] 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 CD8owand CD8hlghsamples. Samples from Fl patients were overrepresented in CD8highsamples compared to CD8low 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 = 3x10-8). 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).

[0209] 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.

[0210] 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).

[0211] 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.). 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.

[0212] ncRNA differentially expressed CD8highand CD8lowsamples are enriched in ncRNA differentially expressed between polyp frequency groups

[0213] 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 CD8highand 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).

[0214] Discussion:

[0215] 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 CD8highsamples 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] Example 2:

[0221] An additional analysis was performed on further patients cohorts.

[0222] The studied groups are as follows:

[0223] Samples from healthy tissues

[0224] 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)

[0225] SSL: Sessile Serrated Lesion (precancer)

[0226] LG or LG. AP: Low Grade Adenomatous Polyp (precancer)

[0227] HG or HG. AP: High Grade Adenomatous Polyp (precancer)

[0228] The following Tables show markers that are differentially expressed between samples from these specific groups.

[0229] 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”).

[0230] The following marker lists are further provided: List Al: Markers differentially expressed in Fl group as compared to (vs) F2F3 group List A2: Fl vs F2F3

[0231] List B: Precancer (HP+SSL+LG+HG) vs sain (UP in Precancer)

[0232] List CL Cancer vs sain (UP in cancer)

[0233] List C2: HG. AP vs sain

[0234] List C3: LG. AP vs sain

[0235] List C4: Cancer vs LG. AP

[0236] List C5: Cancer vs HG. AP

[0237] List C6: HG. AP vs LG. AP

[0238] List C7: HG. AP + LG. AP vs sain

[0239] List Overlap Al+B: gene UP in Precancer AND having significant association with precancer rate / year

[0240] List Overlap A2+B: gene UP in Precancer AND having significant association with precancer rate / year

[0241] lists overlap Cl, C2, C3

[0242] Lists overlap C4, C5, C6

[0243] lists overlap C2, C6

[0244] Intersection and combination

[0245] Table 2: List B of t-test Results for comparison between precancer vs healthy

[0246]

[0247] CADPS 3.66e-10 Up 50.3445(42.7879-57.9011) 20.125(15.1872-25.0628) CEMIP 6.57e-10 Up 86.1765(71.1568-101.1961) 24.8929(13.8857-35.9) FERMT1 6.87e-10 Up 515.6387(457.5017-573.7757) 233.0179(170.789-295.2467) MSLN 7.54e-10 Up 22.3277(16.7564-27.899) 3.2143(2.0568-4.3718)

[0248] 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)

[0249] CCNO 3.25e-09 Up 19.8151(17.0598-22.5704) 8.625(6.3673-10.8827)

[0250] 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)

[0251] 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)

[0252] LINC00858 1.28e-08 Up 3.4118(2.6469-4.1766) 0.75(0.307-1.193)

[0253] 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)

[0254] 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)

[0255] CYP4X1 2.09e-08 Up 34.9748(26.929-43.0206) 9.25(6.1931-12.3069)

[0256] MDFI 2.10e-08 Up 2.1849(1.809-2.5608) 0.7857(0.4981-1.0733)

[0257] 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)

[0258] 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)

[0259] 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)

[0260] PF4 1.48e-07 Up 8.8908(6.8754-10.9061) 2.4821(1.3334-3.6309)

[0261] TDGF1P3 1.65e-07 Up 3.9664(3.2157-4.7171) 1.375(0.8028-1.9472)

[0262] 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)

[0263] 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)

[0264] 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)

[0265] PCSK1 2.95e-07 Up 56.2857(39.7721-72.7993) 10.5714(8.1578-12.9851) ASCL2 3.1 le-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) 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)

[0266] TEX454.75e-07 Up 4.5882(3.7773-5.3992) 1.7857(1.0973-2.4741)

[0267] EDAR 5.40e-07 Up 7.4202(5.9427-8.8977) 2.8929(2-3.7857)

[0268] 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)

[0269] 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) 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)

[0270] 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)

[0271] 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)

[0272] XKR9 1.31e-06 Up 10.8908(8.8852-12.8964) 4.4821(2.9214-6.0428)

[0273] 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) GATA2-AS1 2.07e-06 Up 6.9664(5.485-8.4478) 2.375(1.2532-3.4968) 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)

[0274] LINC025772.25e-06 Up 1.042(0.7058-1.3782) 0.1607(0.0491-0.2723) 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)

[0275] 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)

[0276] 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)

[0277] 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)

[0278] 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)

[0279] C4BPB 4.84e-06 Up 27.5294(23.1546-31.9043) 12.6786(8.2345-17.1227) FEZF1-AS1 5.24e-06 Up 6.6723(4.722-8.6226) 1.5357(0.6025-2.469)

[0280] 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)

[0281] 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) LRRC367.13e-06 Up 4.437(3.5233-5.3507) 1.8393(1.1999-2.4787)

[0282] 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) 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)

[0283] FIRRE l.l le-05 Up 5.1933(3.893-6.4936) 1.9643(1.4215-2.5071)

[0284] FSIP2-AS2 1.13e-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) AC002057.2 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) MSX1 1.24e-05 Up 29.7563(21.1247-38.3879) 8.7143(5.4705-11.9581) TFAP2A-AS1 1.32e-05 Up 1.3613(0.9783-1.7444) 0.3571(0.132-0.5822) ULBP3 1.34e-05 Up 7.0504(5.4862-8.6147) 3(2.1244-3.8756)

[0285] CCDC33 1.35e-05 Up 0.9916(0.6732-1.31) 0.1964(0.0482-0.3446) 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)

[0286] FZD9 1.50e-05 Up 2.1765(1.5329-2.8201) 0.6429(0.4297-0.8561)

[0287] 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)

[0288] AL 133297.22.13e-05 Up 1.916(1.4177-2.4143) 0.6607(0.3844-0.937)

[0289] KLK122.27e-05 Up 6.5714(4.5525-8.5903) 1.7143(0.8272-2.6013)

[0290] PKD1L3 2.33e-05 Up 0.9664(0.661-1.2717) 0.2321(0.0971-0.3672)

[0291] 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)

[0292] 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)

[0293] 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)

[0294] CCDC604.99e-05 Up 3.7731(2.9228-4.6234) 1.625(1.0505-2.1995)

[0295] NXF3 5.63e-05 Up 8.2101(5.8522-10.568) 2.3214(0.7498-3.893)

[0296] RNU1-30P 7.25e-05 Up 1.5126(1.201-1.8242) 0.6071(0.2937-0.9206)

[0297] 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)

[0298] PNPLA3 8.05e-05 Up 5.8067(4.3677-7.2457) 2.2321(1.2198-3.2445)

[0299] 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)

[0300] DLX69.11e-05 Up 2.3697(1.5677-3.1718) 0.5893(0.229-0.9496)

[0301] CHST49.29e-05 Up 1.5714(0.9672-2.1756) 0.2857(0.0966-0.4748)

[0302] 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)

[0303] C2orf70 l.lle-04 Up 3.7143(3.0005-4.4281) 1.6964(0.978-2.4149)

[0304] 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)

[0305] 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)

[0306] 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)

[0307] REGIB 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)

[0308] 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)

[0309] CLIC3 2.90e-04 Up 5.8824(4.565-7.1997) 2.7679(1.7351-3.8006)

[0310] SIOOP 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)

[0311] 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)

[0312] 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)

[0313] KCTD164.13e-04 Up 9.6891(6.0588-13.3194) 2.4643(0.8543-4.0743)

[0314] EVX1 4.19e-04 Up 2.6639(1.7906-3.5371) 0.8571(0.3769-1.3374)

[0315] 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)

[0316] 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) GRM86.10e-04 Up 6.1849(5.0473-7.3225) 3.1786(1.9038-4.4533)

[0317] 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)

[0318] ZIC20.001 Up 17.084(10.0708-24.0973) 3.8929(0.2356-7.5501)

[0319] CNTD20.001 Up 4.0336(2.6431-5.4242) 1.2321(0.2822-2.182)

[0320] SOX1 0.001 Up 2.3782(1.206-3.5503) 0.3571(0.0754-0.6388)

[0321] FIBCD1 0.001 Up 14.3782(9.3139-19.4424) 5.0893(2.7584-7.4202)

[0322] OTX1 0.001 Up 1.916(1.275-2.5569) 0.6071(0.1428-1.0715)

[0323] TNFSF90.001 Up 6.5798(3.7005-9.4592) 1.6429(0.9475-2.3383)

[0324] 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)

[0325] PLA2G30.002 Up 1.8403(1.2397-2.441) 0.6071(0.1235-1.0907)

[0326] 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) AC093817.20.002 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) LINC015940.002 Up 2.2269(1.6739-2.7798) 1(0.4406-1.5594)

[0327] 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)

[0328] NPW 0.003 Up 5.7815(4.0065-7.5566) 2.4643(1.2451-3.6835)

[0329] 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)

[0330] NAT80.003 Up 2.9916(1.6723-4.3109) 0.9107(0.4826-1.3388)

[0331] ZIC50.004 Up 4.5882(2.4431-6.7333) 1.0536(0.0215-2.0856)

[0332] SNRPEP40.004 Up 3.3361(2.3163-4.356) 1.4107(0.5688-2.2526)

[0333] 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)

[0334] REN 0.005 Up 2.4706(1.3068-3.6344) 0.6429(0.1414-1.1443)

[0335] 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)

[0336] NP SRI 0.006 Up 2.5798(1.6822-3.4774) 0.7857(-0.1245-1.696)

[0337] 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)

[0338] DCDC20.009 Up 6.916(5.0819-8.75) 3.7321(2.2091-5.2552)

[0339] REGIA 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)

[0340] 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)

[0341] AFAP1-AS1 0.018 Up 1.916(0.7881-3.0438) 0.5179(0.2429-0.7928)

[0342]

[0343] Table 3: List B-l of t-test Results for comparison between precancer vs healthy (only with ncRNA without protein coding)

[0344]

[0345] AC020891.23.62e-07 Up 1.1765(0.9359-1.4171) 0.375(0.194-0.556) LINC013578.52e-07 Up 2.3361(1.8493-2.8229) 0.75(0.3704-1.1296) LINC00853 1.12e-06 Up 1.7731(1.496-2.0502) 0.75(0.46-1.04) AC104088.21.14e-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) AC124067.41.22e-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-AS1 5.24e-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 l.lle-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) AC104088.3 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) AC007608.41.94e-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) AL354743.2 8.89e-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) LINC01833 2.52e-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) AC124067.3 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) 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~l.99)

[0346]

[0347] Table 4: List B-2 of t-test Results for comparison between precancer vs healthy (only with protein coding)

[0348]

[0349] RNF43 1.50e-09 Up 125.4706(107.3441-143.5971) 48.9821(33.6021-64.3622) EPHX43.08e-09 Up 11.6723(9.3364-14.0082) 2.9286(1.4233-4.4339)

[0350] CCNO 3.25e-09 Up 19.8151(17.0598-22.5704) 8.625(6.3673-10.8827)

[0351] ITGA63.63e-09 Up 919.4202(810.1601-1028.6802) 439.5714(332.9796-546.1633) SH3TC24.44e-09 Up 7.3025(6.2598-8.3452) 2.7321(1.7063-3.7579)

[0352] 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)

[0353] KLRK1 1.23e-08 Up 4.563(3.6741-5.4519) 1.5(1.0102-1.9898)

[0354] 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)

[0355] LGR61.96e-08 Up 18.7059(15.4692-21.9426) 7.4464(5.4647-9.4282)

[0356] CYP4X1 2.09e-08 Up 34.9748(26.929-43.0206) 9.25(6.1931-12.3069)

[0357] MDFI 2.10e-08 Up 2.1849(1.809-2.5608) 0.7857(0.4981-1.0733)

[0358] 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)

[0359] 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)

[0360] 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)

[0361] 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)

[0362] 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)

[0363] 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)

[0364] 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)

[0365] 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)

[0366] 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)

[0367] ED AR 5.40e-07 Up 7.4202(5.9427-8.8977) 2.8929(2-3.7857)

[0368] 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)

[0369] 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) ETV49.27e-07 Up 25.4958(18.9225-32.0691) 6.9286(3.9689-9.8882)

[0370] 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)

[0371] XKR91.31e-06 Up 10.8908(8.8852-12.8964) 4.4821(2.9214-6.0428)

[0372] 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)

[0373] KLK102.50e-06 Up 17.1933(12.2415-22.145) 4.0893(2.1845-5.9941)

[0374] 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)

[0375] 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)

[0376] 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)

[0377] 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) LRRC367.13e-06 Up 4.437(3.5233-5.3507) 1.8393(1.1999-2.4787)

[0378] SLC35D39.41e-06 Up 2.2605(1.5093-3.0118) 0.4643(0.2876-0.6409)

[0379] 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)

[0380] MSX1 1.24e-05 Up 29.7563(21.1247-38.3879) 8.7143(5.4705-11.9581)

[0381] ULBP3 1.34e-05 Up 7.0504(5.4862-8.6147) 3(2.1244-3.8756)

[0382] CCDC33 1.35e-05 Up 0.9916(0.6732-1.31) 0.1964(0.0482-0.3446)

[0383] 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)

[0384] FZD91.50e-05 Up 2.1765(1.5329-2.8201) 0.6429(0.4297-0.8561)

[0385] KLK122.27e-05 Up 6.5714(4.5525-8.5903) 1.7143(0.8272-2.6013)

[0386] PKD1L32.33e-05 Up 0.9664(0.661-1.2717) 0.2321(0.0971-0.3672)

[0387] 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)

[0388] CCDC604.99e-05 Up 3.7731(2.9228-4.6234) 1.625(1.0505-2.1995)

[0389] 0NXF35.63e-05 Up 8.2101(5.8522-10.568) 2.3214(0.7498-3.893)

[0390] 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)

[0391] PI38.09e-05 Up 92.9916(63.0363-122.9469) 26.875(14.6211-39.1289)

[0392] DLX69.1 le-05 Up 2.3697(1.5677-3.1718) 0.5893(0.229-0.9496)

[0393] CHST49.29e-05 Up 1.5714(0.9672-2.1756) 0.2857(0.0966-0.4748)

[0394] SLC22A11 9.57 e-05 Up 3.9748(2.839-5.1105) 1.1964(0.4079-1.985)

[0395] 7 C2orf70 l.lle-04 Up 3.7143(3.0005-4.4281) 1.6964(0.978-2.4149)

[0396] 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 REGIB 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)

[0397] 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)

[0398] 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)

[0399] KCTD164.13e-04 Up 9.6891(6.0588-13.3194) 2.4643(0.8543-4.0743)

[0400] 0EVX1 4.19e-04 Up 2.6639(1.7906-3.5371) 0.8571(0.3769-1.3374)

[0401] 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)

[0402] CBX24.76e-04 Up 3.4034(2.2015-4.6053) 1.1071(0.687-1.5273)

[0403] GRM86.10e-04 Up 6.1849(5.0473-7.3225) 3.1786(1.9038-4.4533)

[0404] MMP77.65e-04 Up 39.7227(26.7145-52.7309) 12.4821(3.505-21.4593)

[0405] NOS2 7.92e-04 Up 41.916(32.0405-51.7914) 17.5(7.2993-27.7007)

[0406] 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)

[0407] ZIC20.001 Up 17.084(10.0708-24.0973) 3.8929(0.2356-7.5501)

[0408] 0 CNTD2 0.001 Up 4.0336(2.6431-5.4242) 1.2321(0.2822-2.182)

[0409] 1 SOX1 0.001 Up 2.3782(1.206-3.5503) 0.3571(0.0754-0.6388)

[0410] FIBCD1 0.001 Up 14.3782(9.3139-19.4424) 5.0893(2.7584-7.4202)

[0411] OTX1 0.001 Up 1.916(1.275-2.5569) 0.6071(0.1428-1.0715)

[0412] TNFSF90.001 Up 6.5798(3.7005-9.4592) 1.6429(0.9475-2.3383)

[0413] 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)

[0414] PLA2G3 0.002 Up 1.8403(1.2397-2.441) 0.6071(0.1235-1.0907)

[0415] 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)

[0416] 1 PRKCG 0.002 Up 1.7479(1.1448-2.351) 0.7143(0.4656-0.963)

[0417]

[0418] _

[0419] Table 5: List C2 of t-test Results for comparison between HG. AP vs healthy

[0420]

[0421] KIAA15498.46e-06 Up 29.7083(22.8412-36.5755) 10.2857(6.7993-13.7721) AGT 1.10e-05 Up 45.2917(33.2214-57.3619) 12.625(9.5522-15.6978)

[0422] MET 1.15e-05 Up 154.4583(117.0271-191.8896) 52.875(39.7235-66.0265) EPHX4 1.15e-05 Up 19.0417(13.0667-25.0166) 2.9286(1.4233-4.4339)

[0423] 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)

[0424] 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)

[0425] RAB15 2.22e-05 Up 72.1667(54.0123-90.3211) 25.4464(20.7244-30.1685) BACE2 2.23e-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)

[0426] MDFI 2.58e-05 Up 3.5833(2.4842-4.6825) 0.7857(0.4981-1.0733)

[0427] AXIN2 2.63e-05 Up 349.4167(241.5513-457.2821) 75.75(51.6046-99.8954)

[0428] SP5 2.64e-05 Up 24.7917(16.7672-32.8161) 4.4464(2.7574-6.1355)

[0429] LIPG 2.68e-05 Up 82.5833(59.4574-105.7093) 23.8929(17.9596-29.8261) CDCA7 2.84e-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)

[0430] 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)

[0431] C2 4.14e-05 Up 44.5(30.6627-58.3373) 10.4107(6.2828-14.5386)

[0432] CKAP2 4.15e-05 Up 97.25(71.1099-123.3901) 32.6964(24.1583-41.2345)

[0433] CKS2 4.41e-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)

[0434] TGFBI 4.50e-05 Up 580.875(406.6229-755.1271) 155.4643(109.1406-201.788) HOXA9 4.78e-05 Up 199.625(150.0846-249.1654) 77.5(57.9288-97.0712)

[0435] ETS2 5.00e-05 Up 921.5(693.1834-1149.8166) 361.5(274.0043-448.9957) LINC01124 5.04e-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) PROXI 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)

[0436] 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)

[0437] EFNA3 7.80e-05 Up 36.625(24.6856-48.5644) 8.7857(6.0486-11.5228)

[0438] 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)

[0439] AC090116.1 8.43e-05 Up 6.2917(3.9672-8.6161) 0.8929(0.285-1.5007)

[0440] 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)

[0441] MELK 1.05e-04 Up 55.375(38.7436-72.0064) 17.1964(11.8794-22.5135)

[0442] 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)

[0443] 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)

[0444] 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)

[0445] 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)

[0446] SLCO4A1-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)

[0447] 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) SLCO5A1 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)

[0448] CXCL3 5.29e-04 Up 342.5(201.0989-483.9011) 63.0357(25.1988-100.8727) ALKALI 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)

[0449] SALL47.32e-04 Up 11.9167(7.5162-16.3172) 3.5(2.3479-4.6521)

[0450] 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)

[0451] SLC6A6 8.80e-04 Up 15.25(9.5042-20.9958) 4.5179(3.2432-5.7925)

[0452] 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)

[0453] 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)

[0454] E2F70.001 Up 14.5(8.7749-20.2251) 4.0714(3.0263-5.1166)

[0455] LRP40.001 Up 91.5(59.1894-123.8106) 31.4464(20.6421-42.2507) 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)

[0456] 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)

[0457] 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)

[0458] STC20.001 Up 16.0833(8.9488-23.2178) 3.3036(1.8484-4.7587)

[0459] IPO40.001 Up 5.25(3.3979-7.1021) 1.8929(1.3484-2.4373)

[0460] GRIN2B 0.001 Up 34(18.9245-49.0755) 6.75(2.4642-11.0358)

[0461] E2F1 0.001 Up 25.4167(16.4065-34.4268) 9.0357(6.0738-11.9976)

[0462] 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)

[0463] SORD 0.001 Up 25.9167(15.1677-36.6657) 6.7143(4.1025-9.3261)

[0464] XKRX 0.001 Up 4.625(2.8517-6.3983) 1.3929(0.7516-2.0341)

[0465] C17orf770.001 Up 4.8333(2.9299-6.7367) 1.1964(0.1694-2.2234)

[0466] MEX3A 0.001 Up 26.75(16.3318-37.1682) 8.2857(6.3642-10.2072)

[0467] OPRD1 0.001 Up 4.5417(2.5378-6.5455) 1(0.677-1.323)

[0468] GATA2-AS1 0.001 Up 8.625(5.159-12.091) 2.375(1.2532-3.4968)

[0469] 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)

[0470] TMEM211 0.001 Up 5(2.8041-7.1959) 1.1071(0.5603-1.654)

[0471] 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)

[0472] 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)

[0473] CBX20.002 Up 10(4.872-15.128) 1.1071(0.687-1.5273)

[0474] AC007688.1 0.002 Up 2.5417(1.5693-3.514) 0.8214(0.5321-1.1108)

[0475] 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)

[0476] 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)

[0477] LINC009700.002 Up 2.875(1.47-4.28) 0.4643(0.1942-0.7343)

[0478] AC239800.20.002 Up 5.5(3.1506-7.8494) 1.4286(0.763-2.0941)

[0479] RAD51AP20.002 Up 3.25(1.9485-4.5515) 1(0.6462-1.3538)

[0480] HOXB60.002 Up 149.5(97.7795-201.2205) 59.0357(41.458-76.6134) C11orf530.002 Up 9.1667(5.9444-12.3889) 3.5536(2.5009-4.6063)

[0481] TFAP2A-AS1 0.002 Up 2.8333(1.3777-4.289) 0.3571(0.132-0.5822)

[0482] 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)

[0483] 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)

[0484] NOXI 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) 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) OXGR1 0.002 Up 15.7083(8.4397-22.9769) 3.5536(2.4886-4.6186) C2orf700.002 Up 5.8333(3.4039-8.2628) 1.6964(0.978-2.4149) LINC011860.002 Up 3.5(1.8481-5.1519) 0.7321(0.4237-1.0406) EDAR 0.002 Up 11.9583(6.5243-17.3924) 2.8929(2-3.7857)

[0485] 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) SNRPG 0.002 Up 243.4167(154.819-332.0143) 92.0536(59.8856-124.2215) FIRRE 0.002 Up 9(4.7335-13.2665) 1.9643(1.4215-2.5071)

[0486] CDCA20.002 Up 27.2083(16.4413-37.9754) 9.1964(6.3954-11.9974) TUBB 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) 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)

[0487] TG 0.003 Up 2.5(1.4289-3.5711) 0.7143(0.3845-1.0441)

[0488] CCL200.003 Up 261.125(134.0371-388.2129) 52.9643(28.3929-77.5356) RPS7P100.003 Up 105.3333(64.3566-146.3101) 36.875(23.4319-50.3181) 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) AC036176.3 0.003 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) CHRNA50.003 Up 9.5833(5.9277-13.239) 3.5714(2.5016-4.6412) LINC018070.003 Up 3.375(1.3834-5.3666) 0.1786(-0.0063~0.3635) BMP70.003 Up 28.75(16.4426-41.0574) 8.8929(6.7906-10.9951) RPS4XP11 0.003 Up 69.125(42.6343-95.6157) 25.25(16.0595-34.4405) CPNE70.003 Up 14.4583(7.2084-21.7082) 2.8036(1.66-3.9471) AC007342.40.003 Up 2.0833(1.1522-3.0145) 0.5714(0.3439-0.799) KLHL320.003 Up 8.4583(5.0054-11.9113) 2.8929(2.2336-3.5522) 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)

[0489] PBK 0.003 Up 60.125(34.9897-85.2603) 19.5536(13.4325-25.6747) 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) 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) 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) GAPLINC 0.004 Up 4.2917(2.4054-6.1779) 1.25(0.6808-1.8192) FAM167A 0.004 Up 7.2083(4.5817-9.835) 2.875(1.8086-3.9414) 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) LINC017300.004 Up 4.8333(2.7923-6.8743) 1.625(1.2211-2.0289) 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) 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) SNORA330.004 Up 4.875(2.5279-7.2221) 1.1964(0.6746-1.7183) 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) AC016735.1 0.004 Up 1.7917(1.0345-2.5489) 0.5893(0.3351-0.8435) 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) 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) 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)

[0490] 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)

[0491] 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)

[0492] GZMB 0.005 Up 9.75(5.3016-14.1984) 2.9821(1.9717-3.9926)

[0493] OR2I1P 0.005 Up 3.6667(1.7551-5.5782) 0.7679(0.3723-1.1634)

[0494] 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)

[0495] 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)

[0496] 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)

[0497] 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)

[0498] NPFFR1 0.006 Up 5.5417(2.6482-8.4352) 1.3036(0.8645-1.7426)

[0499] KLK100.006 Up 18.3333(8.6475-28.0191) 4.0893(2.1845-5.9941)

[0500] 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)

[0501] 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)

[0502] NPSR1-AS1 0.007 Up 7.625(3.0945-12.1555) 0.9821(-0.0257~1.99)

[0503] 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)

[0504] 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)

[0505] 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) KLF160.008 Up 14.625(8.5736-20.6764) 5.6964(3.4495-7.9434)

[0506] IER30.008 Up 12.75(6.5387-18.9613) 3.9286(2.9112-4.9459)

[0507] 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)

[0508] 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)

[0509] 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)

[0510] PAX90.009 Up 5.5(2.8178-8.1822) 1.7143(0.942-2.4866)

[0511] 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)

[0512] 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)

[0513] 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)

[0514] 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)

[0515] ULBP30.014 Up 11.9167(5.0535-18.7798) 3(2.1244-3.8756) 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)

[0516] 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)

[0517] NPSR1 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)

[0518] DLX60.017 Up 4.5833(1.3773-7.7893) 0.5893(0.229-0.9496)

[0519] CHI3L1 0.017 Up 19.75(10.6685-28.8315) 6.9643(1.5465-12.382) KRT800.017 Up 16.375(8.3827-24.3673) 4.4643(-l.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)

[0520] RBM8B 0.019 Up 4.75(2.8606-6.6394) 2.2143(1.2579-3.1707)

[0521] 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)

[0522] 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)

[0523] 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)

[0524] 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)

[0525] NOS20.022 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)

[0526] 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)

[0527] MCIDAS 0.025 Up 1.25(0.49-2.01) 0.3393(0.127-0.5516)

[0528] 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)

[0529] ZIC20.027 Up 37.6667(8.2598-67.0735) 3.8929(0.2356-7.5501)

[0530] AL589669.1 0.027 Up 7.8333(3.2894-12.3773) 2.5536(1.553-3.5542)

[0531] FOXD1 0.027 Up 3.25(0.8998-5.6002) 0.5536(0.2561-0.851)

[0532] 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)

[0533] CASC80.028 Up 4.8333(1.6767-7.99) 1.1607(0.3749-1.9465)

[0534] PPIAP220.028 Up 12.875(5.6515-20.0985) 4.4107(2.3365-6.485)

[0535] TRIM720.028 Up 14.9583(3.0641-26.8526) 1.4107(0.2199-2.6016)

[0536] 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)

[0537] KLRK1 0.029 Up 3.625(1.7958-5.4542) 1.5(1.0102-1.9898)

[0538] 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)

[0539] 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)

[0540] APLN 0.030 Up 9.9583(2.281-17.6357) 1.3571(0.7184-1.9959)

[0541] 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)

[0542] 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)

[0543] KLK60.033 Up 8.7083(3.7378-13.6789) 2.6071(-0.079~5.2933)

[0544] AMH 0.034 Up 4.4583(1.6135-7.3032) 1.2321(0.3565-2.1078)

[0545] PRKCG 0.034 Up 3.3333(0.9393-5.7274) 0.7143(0.4656-0.963)

[0546] AC007493.1 0.034 Up 2.7917(0.7956-4.7878) 0.5357(-0.0917~1.1632)

[0547] ASCL50.035 Up 1.4167(0.4057-2.4276) 0.3036(0.113-0.4941)

[0548] 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)

[0549] FBXL160.035 Up 9.7917(3.2607-16.3226) 2.6429(1.5566-3.7291)

[0550] LINC015550.036 Up 1.75(0.5284-2.9716) 0.4107(0.1565-0.6649)

[0551] 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)

[0552] PF40.038 Up 7.625(2.9067-12.3433) 2.4821(1.3334-3.6309)

[0553] 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)

[0554] AC002367.1 0.040 Up 0.875(0.1672-1.5828) 0.125(0.0356-0.2144)

[0555] SLC22A11 0.040 Up 5.2917(1.4649-9.1184) 1.1964(0.4079-1.985)

[0556] CXCL1 0.041 Up 430.5(90.8071-770.1929) 71.6429(22.9354-120.3504)

[0557] GAD1 0.041 Up 4(1.1935-6.8065) 1.0179(0.4714-1.5643)

[0558] KRT230.042 Up 18(3.7585-32.2415) 2.875(-0.2822~6.0322)

[0559] NPW 0.042 Up 9.875(2.8429-16.9071) 2.4643(1.2451-3.6835)

[0560] DHRS20.042 Up 5.4167(1.4342-9.3992) 1.2321(0.6151-1.8492)

[0561] DNAH20.043 Up 8.5(1.4551-15.5449) 1.1786(0.6858-1.6713)

[0562] AREG 0.043 Up 134.0417(43.7691-224.3142) 39.2321(22.9964-55.4679)

[0563] SOX1 0.043 Up 5.7083(0.545-10.8717) 0.3571(0.0754-0.6388)

[0564] AL359075.1 0.043 Up 1.7083(0.3247-3.092) 0.2679(0.1024-0.4333)

[0565] 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)

[0566] AC078993.1 0.046 Up 21.2917(4.3642-38.2191) 3.9107(1.625-6.1964)

[0567] FIBCD1 0.047 Up 28.7917(5.4701-52.1132) 5.0893(2.7584-7.4202)

[0568] TBX180.048 Up 6.7917(1.8125-11.7708) 1.7143(0.8633-2.5653)

[0569] 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)

[0570] PLA2G4D 0.052 Up 7(3.4083-10.5917) 2.625(-0.0654~5.3154) LINC024320.052 Up 10.7083(3.316-18.1007) 3.0893(0.7871-5.3915)

[0571] ZIC50.054 Up 10.0833(0.9349-19.2318) 1.0536(0.0215-2.0856) 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)

[0572] 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)

[0573] 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)

[0574] 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)

[0575] KISS1R 0.068 Up 1.8333(0.2258-3.4409) 0.3393(0.1532-0.5254)

[0576] 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)

[0577] MSH40.072 Up 2.375(0.4956-4.2544) 0.6429(0.3432-0.9425)

[0578] AFAP1-AS1 0.073 Up 5.5(0.0113-10.9887) 0.5179(0.2429-0.7928)

[0579] FEZF1 0.075 Up 5.5833(-0.2676~11.4343) 0.3036(0.0538-0.5533)

[0580] LEMD1 0.076 Up 4.75(-0.2093~9.7093) 0.2857(0.0121-0.5594)

[0581] USF1 0.076 Up 3.7917(0.4996-7.0837) 0.8036(0.2893-1.3179)

[0582] GRM80.076 Up 6.25(3.048-9.452) 3.1786(1.9038-4.4533)

[0583] H3F3AP60.077 Up 2.125(0.093-4.157) 0.3036(0.1793-0.4278)

[0584] 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)

[0585] 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)

[0586] IGFL20.098 Up 5(1.1844-8.8156) 1.5893(0.0481-3.1305)

[0587] EEF1A1P90.099 Up 1.4583(0.0333-2.8834) 0.2679(0.1377-0.398)

[0588] CST1 0.105 Up 5.0417(0.2489-9.8344) 1.0179(-0.204~2.2397)

[0589] TCN1 0.106 Up 43(2.6285-83.3715) 9.3214(-0.4532~19.0961)

[0590] ULBP20.109 Up 6.5417(-1.0519-14.1352) 0.4107(0.1954-0.626)

[0591] IL 1 A 0.109 Up 5.75(-0.0868~l 1.5868) 1 (0.2023-1.7977)

[0592] 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)

[0593] AL022068.1 0.121 Up 5(0.8646-9.1354) 1.7143(0.8496~2.579)

[0594] 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)

[0595] 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)

[0596] MT-TD 0.139 Up 3.2917(0.1208-6.4626) 0.8929(0.2276-1.5581)

[0597] FZD90.143 Up 2.0833(0.1267-4.04) 0.6429(0.4297-0.8561)

[0598] UCA1 0.150 Up 17.4583(8.6633-26.2534) 8.2857(-l.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)

[0599]

[0600] Table 6: List C2-1 of t-test Results for comparison between HG. AP vs healthy (only with ncRNA without protein coding)

[0601]

[0602] LINC017030.001 Up 2(1.2847-2.7153) 0.6964(0.4125-0.9804) 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) AC007688.1 0.002 Up 2.5417(1.5693-3.514) 0.8214(0.5321-1.1108) 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)

[0603] 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)

[0604] 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)

[0605] 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)

[0606]

[0607] Table 7: List C2-2 of t-test Results for comparison between HG. AP vs healthy (only with protein coding)

[0608]

[0609] 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)

[0610] 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)

[0611] RAB15 2.22e-05 Up 72.1667(54.0123-90.3211) 25.4464(20.7244-30.1685) BACE2 2.23e-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)

[0612] AXIN2 2.63e-05 Up 349.4167(241.5513-457.2821) 75.75(51.6046-99.8954)

[0613] SP5 2.64e-05 Up 24.7917(16.7672-32.8161) 4.4464(2.7574-6.1355)

[0614] LIPG 2.68e-05 Up 82.5833(59.4574-105.7093) 23.8929(17.9596-29.8261) CDCA7 2.84e-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)

[0615] C2 4.14e-05 Up 44.5(30.6627-58.3373) 10.4107(6.2828-14.5386)

[0616] CKAP2 4.15e-05 Up 97.25(71.1099-123.3901) 32.6964(24.1583-41.2345)

[0617] CKS2 4.41e-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)

[0618] TGFBI 4.50e-05 Up 580.875(406.6229-755.1271) 155.4643(109.1406-201.788) HOXA9 4.78e-05 Up 199.625(150.0846-249.1654) 77.5(57.9288-97.0712)

[0619] ETS2 5.00e-05 Up 921.5(693.1834-1149.8166) 361.5(274.0043-448.9957) LINC01124 5.04e-05 Up 2.625(1.8903-3.3597) 0.8214(0.5321-1.1108)

[0620] 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)

[0621] 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)

[0622] EFNA3 7.80e-05 Up 36.625(24.6856-48.5644) 8.7857(6.0486-11.5228)

[0623] 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)

[0624] 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)

[0625] MELK 1.05e-04 Up 55.375(38.7436-72.0064) 17.1964(11.8794-22.5135)

[0626] 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)

[0627] 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)

[0628] 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)

[0629] 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)

[0630] NEK2 1.53e-04 Up 49.375(33.3499-65.4001) 13.8571(9.2777-18.4366)

[0631] 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) 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)

[0632] 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)

[0633] 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)

[0634] KIF24 3.40e-04 Up 5.875(4.0692-7.6808) 2.1071(1.4679-2.7464)

[0635] 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) CXCL3 5.29e-04 Up 342.5(201.0989-483.9011) 63.0357(25.1988-100.8727) ALKALI 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)

[0636] SALL47.32e-04 Up 11.9167(7.5162-16.3172) 3.5(2.3479-4.6521)

[0637] CENPI 7.33e-04 Up 12.5417(8.2211-16.8623) 4.25(3.0072-5.4928)

[0638] 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)

[0639] 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)

[0640] SLC6A6 8.80e-04 Up 15.25(9.5042-20.9958) 4.5179(3.2432-5.7925)

[0641] 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)

[0642] EGFL69.64e-04 Up 4.5833(2.5376-6.6291) 0.7857(0.2758-1.2957)

[0643] 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) 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)

[0644] E2F70.001 Up 14.5(8.7749-20.2251) 4.0714(3.0263-5.1166)

[0645] LRP40.001 Up 91.5(59.1894-123.8106) 31.4464(20.6421-42.2507)

[0646] 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)

[0647] RRM20.001 Up 237.125(145.5985-328.6515) 71.5(51.039-91.961)

[0648] EPHB3 0.001 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)

[0649] STC20.001 Up 16.0833(8.9488-23.2178) 3.3036(1.8484-4.7587)

[0650] IP040.001 Up 5.25(3.3979-7.1021) 1.8929(1.3484-2.4373)

[0651] GRIN2B 0.001 Up 34(18.9245-49.0755) 6.75(2.4642-11.0358)

[0652] E2F1 0.001 Up 25.4167(16.4065-34.4268) 9.0357(6.0738-11.9976)

[0653] LGR60.001 Up 23.0417(14.3214-31.7619) 7.4464(5.4647-9.4282)

[0654] SORD 0.001 Up 25.9167(15.1677-36.6657) 6.7143(4.1025-9.3261)

[0655] XKRX 0.001 Up 4.625(2.8517-6.3983) 1.3929(0.7516-2.0341)

[0656] C17orf770.001 Up 4.8333(2.9299-6.7367) 1.1964(0.1694-2.2234)

[0657] MEX3A 0.001 Up 26.75(16.3318-37.1682) 8.2857(6.3642-10.2072)

[0658] OPRD1 0.001 Up 4.5417(2.5378-6.5455) 1(0.677-1.323)

[0659] 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)

[0660] 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)

[0661] CBX20.002 Up 10(4.872-15.128) 1.1071(0.687-1.5273)

[0662] 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)

[0663] 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)

[0664] RAD51AP20.002 Up 3.25(1.9485-4.5515) 1(0.6462-1.3538)

[0665] HOXB60.002 Up 149.5(97.7795-201.2205) 59.0357(41.458-76.6134) Cl lorf53 0.002 Up 9.1667(5.9444-12.3889) 3.5536(2.5009-4.6063)

[0666] 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)

[0667] C6orf223 0.002 Up 12.0833(6.582-17.5846) 2.6786(1.3735-3.9837)

[0668] 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)

[0669] 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)

[0670] 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)

[0671] OXGR1 0.002 Up 15.7083(8.4397-22.9769) 3.5536(2.4886-4.6186)

[0672] C2orf700.002 Up 5.8333(3.4039-8.2628) 1.6964(0.978-2.4149)

[0673] EDAR 0.002 Up 11.9583(6.5243-17.3924) 2.8929(2-3.7857)

[0674] 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)

[0675] TUBB 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)

[0676] 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)

[0677] BMP70.003 Up 28.75(16.4426-41.0574) 8.8929(6.7906-10.9951)

[0678] CPNE70.003 Up 14.4583(7.2084-21.7082) 2.8036(1.66-3.9471)

[0679] KLHL320.003 Up 8.4583(5.0054-11.9113) 2.8929(2.2336-3.5522)

[0680] PBK 0.003 Up 60.125(34.9897-85.2603) 19.5536(13.4325-25.6747)

[0681] 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)

[0682] 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)

[0683] 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)

[0684] 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)

[0685] 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)

[0686] 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)

[0687] GZMB 0.005 Up 9.75(5.3016-14.1984) 2.9821(1.9717-3.9926)

[0688] OR2I1P 0.005 Up 3.6667(1.7551-5.5782) 0.7679(0.3723-1.1634)

[0689] 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)

[0690] KIF20A 0.005 Up 25.5833(14.281-36.8857) 8.375(5.5484-11.2016)

[0691] GAPDH 0.005 Up 3.6667(2.0591-5.2742) 1.2143(0.7415-1.6871)

[0692] FGGY 0.006 Up 61.625(30.4357-92.8143) 15.25(11.5858-18.9142)

[0693] WNT20.006 Up 6.8333(2.9439-10.7228) 1.0536(0.3714-1.7357)

[0694] 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)

[0695] NPFFR1 0.006 Up 5.5417(2.6482-8.4352) 1.3036(0.8645-1.7426)

[0696] KLK100.006 Up 18.3333(8.6475-28.0191) 4.0893(2.1845-5.9941)

[0697] TRIB30.006 Up 35.2083(17.5587-52.8579) 9.3214(6.1143-12.5286)

[0698] 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)

[0699] 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)

[0700] EVX1 0.007 Up 5.9167(2.4037-9.4296) 0.8571(0.3769-1.3374)

[0701] HIST1H4I 0.007 Up 6.7917(3.7749-9.8085) 2.2679(1.0905-3.4452)

[0702] 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)

[0703] KLF160.008 Up 14.625(8.5736-20.6764) 5.6964(3.4495-7.9434)

[0704] IER30.008 Up 12.75(6.5387-18.9613) 3.9286(2.9112-4.9459)

[0705] 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)

[0706] RPSA 0.008 Up 393.75(233.1-554.4) 156.4286(92.8064-220.0508)

[0707] TEDC20.008 Up 5.2917(2.7022-7.8812) 1.5714(0.8459-2.297)

[0708] 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)

[0709] 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)

[0710] CHST40.009 Up 3.5417(1.1857-5.8976) 0.2857(0.0966-0.4748)

[0711] 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)

[0712] GDF150.010 Up 232.4167(86.1585-378.6749) 32.1786(22.3441-42.0131) MAP IS 0.010 Up 13.75(7.6546-19.8454) 5.1071(3.0634-7.1509)

[0713] 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)

[0714] OTX1 0.011 Up 4.2917(1.5622-7.0211) 0.6071(0.1428-1.0715)

[0715] SLC35D3 0.011 Up 4.375(1.4368-7.3132) 0.4643(0.2876-0.6409)

[0716] PLK1 0.012 Up 34.5833(19.0864-50.0802) 13.1786(7.9-18.4571)

[0717] 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)

[0718] SMN1 0.012 Up 6.375(3.5035-9.2465) 2.5179(1.8404-3.1953)

[0719] 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)

[0720] 0ST40.014 Up 78.2917(42.5057-114.0776) 29.5(15.7602-43.2398)

[0721] IGFL40.014 Up 1.7917(0.8435-2.7398) 0.5179(0.2073-0.8285)

[0722] ULBP30.014 Up 11.9167(5.0535-18.7798) 3(2.1244-3.8756)

[0723] 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)

[0724] TRIM70.015 Up 23.9167(11.3693-36.464) 7.7143(5.453-9.9756)

[0725] POU6F20.015 Up 6.3333(2.0948-10.5718) 0.9107(0.4419-1.3795) 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)

[0726] 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(5.6112-11.5674)

[0727] CXCL80.016 Up 109.75(39.837-179.663) 20.0357(2.9414-37.1301)

[0728] CNTD20.016 Up 8.75(2.8079-14.6921) 1.2321(0.2822-2.182)

[0729] SLCO1B30.017 Up 28.875(8.0807-49.6693) 2.8571(1.1973-4.517)

[0730] NPSR1 0.017 Up 4.8333(1.6865-7.9801) 0.7857(-0.1245-1.696)

[0731] 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)

[0732] DLX60.017 Up 4.5833(1.3773-7.7893) 0.5893(0.229-0.9496)

[0733] CHI3L1 0.017 Up 19.75(10.6685-28.8315) 6.9643(1.5465-12.382)

[0734] KRT800.017 Up 16.375(8.3827-24.3673) 4.4643(-l.3898-10.3184)

[0735] CALR 0.017 Up 34.7083(18.8233-50.5933) 13.7679(7.1888-20.3469)

[0736] REG1B 0.018 Up 389(84.2356-693.7644) 12.8036(-3.3621-28.9692)

[0737] CACNG80.018 Up 5.1667(1.7985-8.5348) 0.9821(0.4805-1.4838)

[0738] NT5DC20.018 Up 6.625(2.5106-10.7394) 1.5(0.699-2.301)

[0739] PI30.019 Up 144.75(48.7887-240.7113) 26.875(14.6211-39.1289)

[0740] UBE2S 0.019 Up 7(2.8032-11.1968) 1.8393(1.0771-2.6015)

[0741] ACAT20.020 Up 3.4583(1.9082-5.0085) 1.4464(0.7749-2.118)

[0742] IL23A 0.021 Up 12.4167(4.2411-20.5923) 2.5(1.2872-3.7128)

[0743] 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)

[0744] LENG80.021 Up 15.9167(8.527-23.3063) 6.6607(4.1267-9.1948)

[0745] ROBO20.021 Up 12.25(5.7915-18.7085) 4.4286(3.3478-5.5093)

[0746] ESM1 0.021 Up 11.8333(3.0996-20.5671) 1.3571(0.7144-1.9999)

[0747] 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)

[0748] PLP20.022 Up 5.7083(2.5669-8.8498) 1.75(0.4741-3.0259)

[0749] NOS20.022 Up 61.7917(25.4724-98.111) 17.5(7.2993-27.7007)

[0750] SIGLEC120.024 Up 2.3333(1.1028-3.5639) 0.8571(0.5168-1.1975)

[0751] ERFE 0.024 Up 4.5(1.3845-7.6155) 0.8393(0.3527-1.3258)

[0752] MCIDAS 0.025 Up 1.25(0.49-2.01) 0.3393(0.127-0.5516)

[0753] LIF 0.026 Up 15.625(5.6318-25.6182) 4.0357(2.4314-5.6401)

[0754] PLA2G30.027 Up 2.6667(0.9204-4.4129) 0.6071(0.1235-1.0907)

[0755] ZIC20.027 Up 37.6667(8.2598-67.0735) 3.8929(0.2356-7.5501)

[0756] FOXD1 0.027 Up 3.25(0.8998-5.6002) 0.5536(0.2561-0.851)

[0757] 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)

[0758] KLRK1 0.029 Up 3.625(1.7958-5.4542) 1.5(1.0102-1.9898)

[0759] COL11A1 0.029 Up 19.0833(4.7076-33.4591) 2.8036(1.6076-3.9995)

[0760] 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)

[0761] 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)

[0762] KLK60.033 Up 8.7083(3.7378-13.6789) 2.6071(-0.079~5.2933)

[0763] AMH 0.034 Up 4.4583(1.6135-7.3032) 1.2321(0.3565-2.1078)

[0764] PRKCG 0.034 Up 3.3333(0.9393-5.7274) 0.7143(0.4656-0.963)

[0765] ASCL50.035 Up 1.4167(0.4057-2.4276) 0.3036(0.113-0.4941)

[0766] 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)

[0767] FBXL160.035 Up 9.7917(3.2607-16.3226) 2.6429(1.5566-3.7291)

[0768] LINC015550.036 Up 1.75(0.5284-2.9716) 0.4107(0.1565-0.6649)

[0769] PF40.038 Up 7.625(2.9067-12.3433) 2.4821(1.3334-3.6309)

[0770] 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)

[0771] SLC22A11 0.040 Up 5.2917(1.4649-9.1184) 1.1964(0.4079-1.985)

[0772] CXCL1 0.041 Up 430.5(90.8071-770.1929) 71.6429(22.9354-120.3504) GAD1 0.041 Up 4(1.1935-6.8065) 1.0179(0.4714-1.5643)

[0773] KRT230.042 Up 18(3.7585-32.2415) 2.875(-0.2822~6.0322)

[0774] NPW 0.042 Up 9.875(2.8429-16.9071) 2.4643(1.2451-3.6835)

[0775] DHRS20.042 Up 5.4167(1.4342-9.3992) 1.2321(0.6151-1.8492)

[0776] DNAH20.043 Up 8.5(1.4551-15.5449) 1.1786(0.6858-1.6713)

[0777] AREG 0.043 Up 134.0417(43.7691-224.3142) 39.2321(22.9964-55.4679) SOX1 0.043 Up 5.7083(0.545-10.8717) 0.3571(0.0754-0.6388)

[0778] REG1A 0.044 Up 3059(587.3952-5530.6048) 484.5357(112.8535-856.218) C4BPA 0.046 Up 8.875(4.3436-13.4064) 3.6607(1.1494-6.172)

[0779] FIBCD1 0.047 Up 28.7917(5.4701-52.1132) 5.0893(2.7584-7.4202)

[0780] TBX180.048 Up 6.7917(1.8125-11.7708) 1.7143(0.8633-2.5653) 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) PLA2G4D 0.052 Up 7(3.4083-10.5917) 2.625(-0.0654~5.3154)

[0781] ZIC50.054 Up 10.0833(0.9349-19.2318) 1.0536(0.0215-2.0856) CACNA2D20.056 Up 30.3333(12.9027-47.764) 13.2143(10.6908-15.7377) 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)

[0782] TNNT1 0.065 Up 7.875(0.5386-15.2114) 0.9286(-0.1497-2.0069)

[0783] NXF30.066 Up 8.3333(2.0656-14.601) 2.3214(0.7498-3.893)

[0784] 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)

[0785] TRIM290.067 Up 30.25(11.1044-49.3956) 10.3214(0.018-20.6249) KISS1R 0.068 Up 1.8333(0.2258-3.4409) 0.3393(0.1532-0.5254)

[0786] PTP4A30.070 Up 36.125(10.7925-61.4575) 12.6429(9.1157-16.17)

[0787] MSH40.072 Up 2.375(0.4956-4.2544) 0.6429(0.3432-0.9425)

[0788] FEZF1 0.075 Up 5.5833(-0.2676~11.4343) 0.3036(0.0538-0.5533)

[0789] LEMD1 0.076 Up 4.75(-0.2093~9.7093) 0.2857(0.0121-0.5594)

[0790] USF1 0.076 Up 3.7917(0.4996-7.0837) 0.8036(0.2893-1.3179)

[0791] GRM80.076 Up 6.25(3.048-9.452) 3.1786(1.9038-4.4533)

[0792] 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) 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)

[0793] IGFL20.098 Up 5(1.1844-8.8156) 1.5893(0.0481-3.1305)

[0794] CST1 0.105 Up 5.0417(0.2489-9.8344) 1.0179(-0.204~2.2397)

[0795] TCN1 0.106 Up 43(2.6285-83.3715) 9.3214(-0.4532~19.0961)

[0796] ULBP20.109 Up 6.5417(-1.0519-14.1352) 0.4107(0.1954-0.626)

[0797] IL 1 A 0.109 Up 5.75(-0.0868~l 1.5868) 1 (0.2023-1.7977)

[0798] RETNLB 0.114 Up 291.7917(51.7356-531.8477) 99.2321(61.8005-136.6638) REN 0.120 Up 4.375(-0.3809~9.1309) 0.6429(0.1414-1.1443)

[0799] KCTD160.125 Up 12.25(-0.385~24.885) 2.4643(0.8543-4.0743)

[0800] SPP1 0.126 Up 87.0417(-3.6407-177.7241) 16.9107(5.3763-28.4452)

[0801] FZD90.143 Up 2.0833(0.1267-4.04) 0.6429(0.4297-0.8561)

[0802] HIST1H2BF 0.153 Up 3.2917(-0.8671~7.4504) 0.3214(0.1512-0.4916) SLC5A80.157 Up 2.75(0.7802-4.7198) 1.3214(0.8587-1.7842)

[0803] ALPG 0.186 Up 7.5417(-2.2241~17.3074) 1.0893(0.5363-1.6423)

[0804] SPDYE160.222 Up 1.1667(-0.155-2.4884) 0.3571(0.1632-0.5511)

[0805] DCDC20.233 Up 5.7083(2.7264-8.6902) 3.7321(2.2091-5.2552)

[0806] CYP2W1 0.236 Up 50.7917(-25.9813-127.5646) 5.5893(2.9734-8.2051) ATG9B 0.292 Up 6.1667(1.1756-11.1578) 3.4821 (2.2095-4.7547)

[0807] BOLA2B 0.377 Up 3.9583(-2.5351-10.4518) 1.125(0.8018-1.4482)

[0808] LCN150.517 Up 11.5833(-5.9189-29.0856) 5.7857(0.7929-10.7785) S100A20.597 Down 18.4167(10.3183-26.5151) 34.2321(-24.927~93.3913) CXCL100.649 Up 31.1667(18.8446-43.4888) 24.375(-2.8861~51.6361) DSC30.686 Up 33.125(-0.0426~66.2926) 22.7143(-17.3653~62.7938) KLK70.821 Down 7(0.8707-13.1293) 8.5(-3.3104-20.3104) Table 8: List C3 of t-test Results for comparison between LG. AP vs healthy

[0809]

[0810] CACNA2D2 1.05e-07 Up 29.3594(24.3656-34.3531) 13.2143(10.6908-15.7377) SH3TC2 1.05e-07 Up 7.3906(6.1079-8.6733) 2.7321(1.7063-3.7579)

[0811] LGR5 1.08e-07 Up 110.4531(86.2428-134.6634) 29.0536(14.035-44.0721) HOXB-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)

[0812] OLFM42.19e-07 Up 5163.4375(3722.5127-6604.3623) 902.4286(550.5311-1254.326) TEX452.51e-07 Up 5.4844(4.3375-6.6312) 1.7857(1.0973-2.4741)

[0813] OXGR1 2.64e-07 Up 10.4375(8.2078-12.6672) 3.5536(2.4886-4.6186)

[0814] 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)

[0815] CLDN23.89e-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)

[0816] 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)

[0817] CCNO 5.31e-07 Up 18.5156(15.559-21.4722) 8.625(6.3673-10.8827)

[0818] AGT 6.19e-07 Up 29.4688(23.9555-34.982) 12.625(9.5522-15.6978)

[0819] 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)

[0820] 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)

[0821] C17orf77 8.85e-07 Up 6.6562(4.8472-8.4653) 1.1964(0.1694-2.2234)

[0822] 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) FZD99.13e-07 Up 3.1094(2.2191-3.9996) 0.6429(0.4297-0.8561)

[0823] PF4 1.12e-06 Up 11.3594(8.199-14.5198) 2.4821(1.3334-3.6309)

[0824] 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)

[0825] 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)

[0826] 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)

[0827] 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)

[0828] FDXR 1.63e-06 Up 17.7188(14.756-20.6815) 8.6964(6.7332-10.6597)

[0829] FSIP2-AS2 1.63e-06 Up 4.4844(3.554-5.4148) 1.625(0.9881-2.2619)

[0830] TTPA 1.72e-06 Up 20.0625(16.6581-23.4669) 9.75(7.518-11.982)

[0831] RPL10P2 1.88e-06 Up 1.125(0.8119-1.4381) 0.25(0.1125-0.3875)

[0832] 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) GALNT82.00e-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) KSR22.12e-06 Up 7.9688(6.5884-9.3491) 3.6964(2.6906-4.7022)

[0833] AC022075.1 2.15e-06 Up 12.3125(9.8433-14.7817) 5.3393(4.1176-6.5609)

[0834] SP5 2.30e-06 Up 13.4688(10.306-16.6315) 4.4464(2.7574-6.1355)

[0835] 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)

[0836] GAU1 3.50e-06 Up 25.3594(21.1281-29.5906) 12.0714(8.6313-15.5115)

[0837] MB 3.53e-06 Up 16.0781(13.4962-18.66) 8.1071(6.1001-10.1142)

[0838] AC007608.2 3.77e-06 Up 1.6875(1.0873-2.2877) 0.1429(0.0134-0.2723) EGF 3.98e-06 Up 11.0781(8.8301-13.3262) 4.6071(3.1913-6.023)

[0839] ADAM324.03e-06 Up 6.5(5.3785-7.6215) 2.9464(1.9973-3.8955)

[0840] 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) ATOH84.90e-06 Up 29.5312(23.6838-35.3787) 13.0536(9.5308-16.5763) AC027808.24.96e-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) HES56.29e-06 Up 8.2188(6.4277-10.0098) 3.3929(2.4698-4.3159)

[0841] 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)

[0842] CPNE7 7.81e-06 Up 7.2031(5.7129-8.6934) 2.8036(1.66-3.9471)

[0843] 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)

[0844] 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)

[0845] TMEM211 1.06e-05 Up 3.5(2.6233-4.3767) 1.1071(0.5603-1.654)

[0846] 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) PROXI 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)

[0847] 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) AC239800.22.73e-05 Up 5.75(3.9285-7.5715) 1.4286(0.763-2.0941) CERNA22.86e-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)

[0848] C2orfl5 3.73e-05 Up 6.3906(4.9969-7.7843) 3(2.2887-3.7113)

[0849] LINC02163 3.76e-05 Up 1.6094(1.0229-2.1958) 0.25(0.0441-0.4559)

[0850] 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) 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) LINC016595.01e-05 Up 5.6719(4.0095-7.3342) 1.8929(1.3181-2.4676) LINC022545.15e-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)

[0851] 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) RCC2P67.57e-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)

[0852] 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)

[0853] 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 E85e-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)

[0854] 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)

[0855] 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) 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) LINC013576.28e-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) AL023284.27.30e-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) AC010378.29.33e-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) AC097504.20.001 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) LINC011320.001 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) LINC022530.001 Up 2.8438(1.7071-3.9804) 0.6071(-0.1306-1.3449) RPL12P130.001 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) SNORA790.001 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) LINC015940.002 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) AC093817.20.002 Up 1.4688(0.7484-2.1891) 0.2679(0.0311-0.5046) CASC90.002 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) ATP5F1AP30.003 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)

[0856] REGIB 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)

[0857] SOX1 0.003 Up 1.9219(0.9284-2.9154) 0.3571(0.0754-0.6388) LINC024430.003 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) IGFL40.004 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) LINC018330.005 Up 4.1562(2.479-5.8335) 1.5357(0.8719-2.1995) CCDC1960.005 Up 5.4531(3.7066-7.1996) 2.5536(1.5634-3.5437)

[0858] 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) CASC80.005 Up 2.8594(1.9716-3.7471) 1.1607(0.3749-1.9465)

[0859] REN 0.005 Up 2.6406(1.3497-3.9316) 0.6429(0.1414-1.1443)

[0860] SHISA60.005 Up 6.1406(3.7234-8.5579) 2.25(1.0114-3.4886)

[0861] 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) AC024592.20.007 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) AC090578.20.008 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)

[0862] 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) IGLV6-570.010 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)

[0863] 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)

[0864] 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)

[0865] REGIA 0.017 Up 1437.125(745.5756-2128.6744) 484.5357(112.8535-856.218) AC005702.20.017 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)

[0866] GRPR 0.018 Up 1.7969(0.6421-2.9516) 0.3571(0.0801-0.6342)

[0867] TBX180.019 Up 4.5(2.3333-6.6667) 1.7143(0.8633-2.5653)

[0868] LINC024130.020 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) MTATP8P20.021 Up 30.5625(14.9724-46.1526) 10.0714(2.2838-17.859) AL359636.20.021 Up 3.9375(2.4165-5.4585) 1.875(0.983-2.767) RPS2P460.024 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)

[0869] S0X140.026 Up 1.6094(0.8326-2.3862) 0.4821(-0.1454~l.1097)

[0870] CABP70.027 Up 1.7344(0.603-2.8658) 0.4286(0.1898-0.6673)

[0871] 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)

[0872] IGHG20.061 Up 33.4688(5.5982-61.3393) 6.6607(3.5014-9.82)

[0873] IGLV3-100.064 Up 2.75(0.867-4.633) 0.9286(0.4694-1.3878)

[0874] 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)

[0875]

[0876] Table 9: List C3-1 of t-test Results for comparison between LG. AP vs healthy (only with ncRNA without protein coding)

[0877]

[0878] AC022075.1 2.15e-06 Up 12.3125(9.8433-14.7817) 5.3393(4.1176-6.5609) 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) 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)

[0879] 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) AC239800.22.73e-05 Up 5.75(3.9285-7.5715) 1.4286(0.763-2.0941) CERNA22.86e-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) LINC016595.01e-05 Up 5.6719(4.0095-7.3342) 1.8929(1.3181-2.4676) LINC022545.15e-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)

[0880] SCARNA226.1 le-05 Up 16.1875(12.0377-20.3373) 6.375(4.2274-8.5226) RCC2P67.57e-05 Up 1.5781(1.178-1.9782) 0.6071(0.3586-0.8556)

[0881] 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)

[0882] 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) LINC025775.30e-04 Up 1.0625(0.5793-1.5457) 0.1607(0.0491-0.2723) LINC013576.28e-04 Up 2.1094(1.4401-2.7786) 0.75(0.3704-1.1296) AL023284.27.30e-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) AC010378.29.33e-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) AC097504.20.001 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) LINC011320.001 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) LINC022530.001 Up 2.8438(1.7071-3.9804) 0.6071 (-0.1306-1.3449) RPL12P130.001 Up 1.1562(0.844-1.4685) 0.5357(0.3254-0.7461) SNORA790.001 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) LINC015940.002 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) AC093817.20.002 Up 1.4688(0.7484-2.1891) 0.2679(0.0311-0.5046) CASC90.002 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) ATP5F1AP30.003 Up 1.0156(0.5585-1.4727) 0.25(0.0572-0.4428) LINC024430.003 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) LINC018330.005 Up 4.1562(2.479-5.8335) 1.5357(0.8719-2.1995)

[0883] B0K-AS1 0.005 Up 1.8281(0.7511-2.9051) 0.2321(0.0481-0.4162) CASC80.005 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) AC024592.20.007 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) AC090578.20.008 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) IGLV6-570.010 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) AC005702.20.017 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) LINC024130.020 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) MTATP8P20.021 Up 30.5625(14.9724-46.1526) 10.0714(2.2838-17.859) AL359636.20.021 Up 3.9375(2.4165-5.4585) 1.875(0.983-2.767) RPS2P460.024 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)

[0884]

[0885] Table 10: List C3-2 of t-test Results for comparison between LG. AP vs healthy (only with protein coding)

[0886]

[0887] CACNA2D2 1.05e-07 Up 29.3594(24.3656-34.3531) 13.2143(10.6908-15.7377) SH3TC2 1.05e-07 Up 7.3906(6.1079-8.6733) 2.7321(1.7063-3.7579)

[0888] LGR5 1.08e-07 Up 110.4531(86.2428-134.6634) 29.0536(14.035-44.0721)

[0889] ENCI 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) OLFM42.19e-07 Up 5163.4375(3722.5127-6604.3623) 902.4286(550.5311-1254.326) TEX452.51e-07 Up 5.4844(4.3375-6.6312) 1.7857(1.0973-2.4741)

[0890] OXGR1 2.64e-07 Up 10.4375(8.2078-12.6672) 3.5536(2.4886-4.6186)

[0891] HOXA9 3.09e-07 Up 164.0625(138.9488-189.1762) 77.5(57.9288-97.0712) CLDN23.89e-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)

[0892] CCNO 5.31e-07 Up 18.5156(15.559-21.4722) 8.625(6.3673-10.8827)

[0893] AGT 6.19e-07 Up 29.4688(23.9555-34.982) 12.625(9.5522-15.6978)

[0894] 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)

[0895] 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)

[0896] C17orf77 8.85e-07 Up 6.6562(4.8472-8.4653) 1.1964(0.1694-2.2234)

[0897] FZD99.13e-07 Up 3.1094(2.2191-3.9996) 0.6429(0.4297-0.8561)

[0898] PF4 1.12e-06 Up 11.3594(8.199-14.5198) 2.4821(1.3334-3.6309)

[0899] LINC01124 1.25e-06 Up 2.3594(1.8396-2.8791) 0.8214(0.5321-1.1108)

[0900] CELSR3 1.49e-06 Up 9.5(8.0661-10.9339) 4.5893(3.2855-5.893)

[0901] 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)

[0902] TTPA 1.72e-06 Up 20.0625(16.6581-23.4669) 9.75(7.518-11.982)

[0903] SERPINA1 1.91e-06 Up 529.8906(391.8701-667.9112) 154.1786(107.5009-200.8563) GALNT82.00e-06 Up 13.6406(11.193-16.0882) 5.7857(3.8226-7.7488)

[0904] IQANK1 2.07e-06 Up 23.3906(19.4241-27.3571) 11.0179(8.0667-13.969)

[0905] KSR22.12e-06 Up 7.9688(6.5884-9.3491) 3.6964(2.6906-4.7022)

[0906] SP5 2.30e-06 Up 13.4688(10.306-16.6315) 4.4464(2.7574-6.1355)

[0907] SEMA3F 2.64e-06 Up 19.5938(16.3749-22.8126) 10.0893(8.0198-12.1588)

[0908] MB 3.53e-06 Up 16.0781(13.4962-18.66) 8.1071(6.1001-10.1142)

[0909] EGF 3.98e-06 Up 11.0781(8.8301-13.3262) 4.6071(3.1913-6.023)

[0910] ADAM324.03e-06 Up 6.5(5.3785-7.6215) 2.9464(1.9973-3.8955)

[0911] 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)

[0912] ATOH84.90e-06 Up 29.5312(23.6838-35.3787) 13.0536(9.5308-16.5763) AC027808.24.96e-06 Up 2.0938(1.5191-2.6684) 0.5(0.177-0.823)

[0913] MSLN 5.54e-06 Up 22.4688(14.774-30.1635) 3.2143(2.0568-4.3718)

[0914] HES56.29e-06 Up 8.2188(6.4277-10.0098) 3.3929(2.4698-4.3159)

[0915] 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)

[0916] CPNE77.81e-06 Up 7.2031(5.7129-8.6934) 2.8036(1.66-3.9471)

[0917] CARMIL3 8.17e-06 Up 3.5312(2.7669-4.2956) 1.375(0.8629-1.8871)

[0918] SLC22A11 8.66e-06 Up 5.125(3.6526-6.5974) 1.1964(0.4079-1.985)

[0919] GRM88.71e-06 Up 7.9062(6.3241-9.4884) 3.1786(1.9038-4.4533)

[0920] TMEM211 1.06e-05 Up 3.5(2.6233-4.3767) 1.1071(0.5603-1.654)

[0921] 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)

[0922] CRB2 1.41e-05 Up 1.8906(1.4752-2.306) 0.7321(0.4366-1.0277)

[0923] 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)

[0924] CYP19A1 2.95e-05 Up 1.2656(0.9565-1.5748) 0.4643(0.2667-0.6618)

[0925] CCDC33 3.62e-05 Up 1.2188(0.7771-1.6604) 0.1964(0.0482-0.3446) C2orf15 3.73e-05 Up 6.3906(4.9969-7.7843) 3(2.2887-3.7113) 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) 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)

[0926] 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)

[0927] 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)

[0928] 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)

[0929] SALL4 4.22e-04 Up 7.2656(5.5464-8.9849) 3.5(2.3479-4.6521)

[0930] 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)

[0931] 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)

[0932] 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)

[0933] 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)

[0934] 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)

[0935] TMPRSS5 0.003 Up 5.0312(3.3821-6.6804) 2.3393(1.833-2.8455)

[0936] LEMD1 0.003 Up 1(0.612-1.388) 0.2857(0.0121-0.5594)

[0937] REGIB 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)

[0938] SOX1 0.003 Up 1.9219(0.9284-2.9154) 0.3571(0.0754-0.6388)

[0939] CHST4 0.004 Up 1.2969(0.6539-1.9398) 0.2857(0.0966-0.4748)

[0940] C2orf70 0.004 Up 3.3594(2.5028-4.2159) 1.6964(0.978-2.4149)

[0941] CYP4Z1 0.004 Up 1.9375(1.2775-2.5975) 0.7857(0.3749-1.1965)

[0942]

[0943] Table 11: Al list

[0944]

[0945] AL031733.2, TP53I11, AC008915.1, TRMT112, AC006270.1, SLC22A13, 0ST4, AC068896.1, SNRPGP2, AC007292.2, AL731577.1, U2AF1L5, AC012100.2, GPM6A, NCBP2-AS1, KCNJ2, RPL22P6, AC091231.1, MYCBP2-AS1, PL TP, U2AF2, AC093249.2, AP003733.4, CCDC88B, 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, AC020741.1, 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, AC026801.2, RN7SL801P, FBXO24, AL031729.1, CHGB, AL354941.1, ANKRD18B, PPIEL, ATP8A2, MROH3P, HSF1, MRPL53P1, LINC02316, AP003390.2, FABP5P7, Cllorf96, AC026271.1, 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, FBLL1, 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,

[0946]

[0947] Table 12: Al-1 list (only with ncRNA without protein coding)

[0948]

[0949]

[0950] Table 13: Markers in common between Al and B lists

[0951]

[0952] Table 14: A2 list

[0953]

[0954] AL731577.1, U2AF1L5, AC012100.2, GPM6A, NCBP2-AS1, KCNJ2, RPL22P6, AC091231.1, MYCBP2-AS1, PLTP, U2AF2, AC093249.2, AP003733.4, CCDC88B, 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, AC020741.1, 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, AC026801.2, RN7SL801P, FBXO24, AL031729.1, CHGB, AL354941.1, ANKRD18B, PPIEL, ATP8A2, MROH3P, HSF1, MRPL53P1, LINC02316, AP003390.2, FABP5P7, Cllorf96, AC026271.1, 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, FBLL1, 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,

[0955]

[0956] Table 15: A2-2 list (only with protein coding)

[0957]

[0958] Table 16: A2-1 list (only with ncRNA without protein coding)

[0959]

[0960] AL392172.1, TMC01-AS1, AC007000.3, AC087276.1, AC084782.2, AC090739.1, AL691482.3, AC027020.2, AL136984.1, AP005131.6, AP005131.7, AL390195.2, AC087854.1, AC025423.1, AC025423.4, KLF3-AS1, AC040904.1, AC022211.1, AC079174.1, AC073475.1, AP002026.1, 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, SNORA71B, AC007952.4, SNORD3D, SNRK-AS1, SOS1-IT1, RF00012_45, SNORD3G, RF00012_37, RF00012_18, RF01848, RF00012_31, RF00012_12, RF00012_40, RF00012_16, RF00012_5, RF00012_8, RF00012_46, RF00012_25, RF00012_35, RF00012_50, RF00012_43, RF00012_29, RF00012_13, SNORD3H, RF00012_26, RF00012_23, RF00012_17, RF00012_30, RF00012_51, RF00012_42, RF00012_48, RF00012_27, RF00012 1, RF00012_2, RF00012_20, RF00012_17, RF00012_32, RF00012_3, RF00012, RF00012_36, RF00012_14, RF00012_21, RF00012_39, RF00012_38, SNORD3I, RF00012_41, RF00012_47, RF00012_15, 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, RF00019_183, 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, RF00019_191, RF00019_108, RF00019_63, RF00019_214, RF00019_458, RF00019_545, RF00019_417, RF00019_441, RF00019_656, RF00019_513, RF00019_534, RF00019_459, RF00019 11, RF00019_42, RF00019_740, 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_193, RF00019_678, RF00019_161, 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, RF00019_168, RF00019_181, RF00019_504, RF00019_542, RF00019_145, RF00019_533, 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, RF00019_78, RF00019_544, RF00019_73, RF00019_125, RF00019_485, RF00019_238, RF00019_384, RF00019_180, 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, RF00019_130, RF00019_711, 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, RF00019_121, RF00019_404, RF00019_694, RF00019_220, RF00019_26, RF00019_529, RF00019_591, 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, RF00019_736, RF00019_342, RF00019_308, RF00019_373, RF00019_117, RF00019_79, RF00019_733, RF00019_671, RF00019_101, RF00019_203, RF00019_317, RF00019_326, RF00019_427, RF00019_393, RF00019_647, RF00019_713, RF00019_396, RF00019_344, RF00019_692, RF00019_298, RF00019_622, RF00019_77, RF00019_137, RF00019_628, RF00019_207, RF00019_640, RF00019_314, RF00019_553, RF00019_288, RF00019_702, RF00019 62, RF00019_436, RF00019_74, 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, RF00019_182, RF00019_684, RF00019_481, RF00019_619, RF00019_151, RF00019_310, RF00019_570, RF00019_112, 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, RF00019_717, RF00019_595, RF00019_316, RF00019_574, RF00019_277, RF00019_410, RF00019_418, RF00019_469, RF00019_209, RF00019 139, RF00019 302, RF00019 97, RF00019 144, RF00019 467, RF00019 587, RF00019_153, RF00019_627, RF00019_624, RF00019_201, RF00019_368, RF00019_60, RF00019_75, RF00019 54, 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, RF00019_132, RF00019_620, RF00019_483, RF00019_527, RF00019_157, RF00019_476, RF00019_202, RF00019_707, RF00019_716, RF00019_269, RF00019_490, RF00019 22, RF00019 6, RF00019_92, RF00019_107, 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, RF00019_163, 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, RF00019_755, RNY3P12, RF00019_219, RF00019_350, RF00019_681, RF00019_143, RF00019_306, RF00019_567, RF00019_331, RF00019_297, RF00019_73, RF00019_361, RF00019_29, RF00019_475, RF00019_679, RF00019_195, RF00019_743, RF00019_741, RNY3P13, RF00019_407, RF00019_559, RF00019_609, RF00019_221, RF00019_4, RF00019_720, RF00019_71, RF00019_264, RF00019_734, RF00019_78, RF00019_669, RF00019_129, RF00019_704, RF00019_558, RF00019_517, RF00019_236, RF00019_411, RF00019 47, RF00019_728, RF00019_57, RF00019_450, RF00019_737, RF00019_45, RF00019_52, RF00019_82, RF00019_149, RF00019_727, RF00019_334, RF00019_593, RF00019_228, RF00019_731, RF00019_33, RF00019_543, RF00019_134, RF00019_50, RF00019_680, RF00019_12, 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, RF00019_10, RF00019_245, RF00019_695, RF00019 74, RF00019_722, RF00019_723, RF00019_400, RF00019_291, RF00019_123, RF00019_120, RF00019_443, RF00019_539, RF00019J33, RF00019_30, RF00019_205, RF00019_293, RF00019_86, RF00019_719, RF00019_224, RF00019_142, RF00019 88, RF00019 16, RF00019_751, RF00019_327, RF00019_616, RF00019_53, RF00019_136, RF00019_540, RF00019_185, 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, RF00019_127, RF00019_725, 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, RF00019_156, RF00019_746, RF00019_519, RF00019_721, RNY1P14, RF00019_377, RF00019_194, RF00019_267, RF00019_152, RF00019_186, RF00019_576, RF00019_501, RF00019_128, 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, RF00019_7, RF00019_395, RF00019_401, RF00019_465, RF00019_562, RF00019_392, RF00019_718, RF00019_70, RF00019_709, RF00019_216, RF00019_489, RF00019_20, RF00019_745, RF00019 69, RF00019_492, RF00019_491, RF00019_591, RF00019_32, RF00019_403, RF00019_300, RF00019_365, RF00019_522, RF00019_391, RF00019_166, RF00019_551, RF00019_249, RF00019_710, RF00019_606, RF00019_556, RF00019_735, RF00019_352, RF00019_431, RF00019_675, RF00019_571, RF00019_259, RF00019_742, RF00019_89, RF00019_548, RF00019_670, RF00019 8, RF00019 58, RF00019_95, RF00019_516, RF00019_502, RF00019_240, RF00019_646, RF00019_109, RF00019_533, RF00019_602, RF00019_453, RF00019_273, RF00019_65, RF00019_749, RF00019_253, RF00019_468, RF00019_102, RF00019_192, RF00019_461, RF00019_386, RNY4P36, RF00019_72, RF00019_62, RF00019_478, RF00019_445, RF00019_103, RF00019_77, 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, RF00019_140, RF00019_76, RF00019_184, RF00019_523, RF00019_338, RF00019_605, RF00019_687, RF00019_440, RF00019_265, RF00019_266, RF00019 573, RF00019 287, RF00019 464, RF00019 662, RF00019 110, RF00019 318, RF00019_341, RF00019 15, RF00019 715, RF00019_674, RF00019_27, RF00019_248, RF00019_213, RF00019_106, RF00019 76, RF00019_732, RF00019_189, 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, RF00019_697, RF00019 48, RF00019_505, RF00019_635, RF00019_6, RF00019_360, RF00019_701, RF00019_659, RF00019_307, RF00019_200, RF00019_507, RF00019_79, RF00019_455, RF00019_275, RF00019_31, RF00019_651, RF00019_589, AC009812.1, RF00019_454, RF00019 756, RF00019_416, RNY4P37, RF00019_305, RF00019_652, RF00019_420, RF00019 747, RF00019_9, RNY3P15, RF00019_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, RF00019_14, RF00019_730, RF00019_528, RF00019_296, RF00019_150, RF00019 64, RF00019_58, RF00019_615, RF00019_85, RF00019 24, RF00019_217, RF00019_165, RF00019_537, RF00019_372, RF00019_40, RF00019_388, RF00019_583, RF00019_25, RF00019_8, RF00019_658, RF00019_66, RF00019 26, RF00019_599, RF00019_479, RF00019_432, RF00019 98, RF00019_477, RF00019_500, RF00019 55, RF00019_663, RF00019_222, AC010542.4, AC115989.1, RF00019_23, RF00019_690, RF01210_15, SNORD13E, RF01210, RF01210_21, RF01210_12, RF01210_26, RF01210_3, RF01210_7, RF01210_30, SNORD13P1, RF01210_13, RF01210_24, RF01210_23, RF01210_8, RF01210_20, RF01210_4, RF01210_22, RF01210_2, RF01210_28, RF01210_10, RF01210_27, RF01210_19, RF01210_25, SNORD13D, RF01210_14, RF01210_6, RF01210_29, RF01210_18, RF01210_17, SNORD13P3, RF01210_9, RF01210 1, RF01210_5, LINC01998, RF01210_16, MIR559, IGHGP, AC000111.2, AC002075.2, AC005042.1, AC007041.1, AC007386.1, AC008427.1, AC009263.1, AC010733.1, AC016712.1, RPS29P8, RPL26P19, AC069154.1, AC079250.1, AC092106.1, RPL22P16, 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, IPO8P1, 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, AC115223.1, 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, RNU6-611P, RNU6-638P, RNU6-658P, RNU6-920P, RNU6-957P, RNU6-998P, RNU7-40P, SCARNA13, SCARNA3, SCARNA4, SCARNA7, SNORA31, RF00322 9, RF00322 6, RF00322_5, RF00322_8, RF00322 8, RF00322_26, RF00322_11, RF00322_14, RF00322_10, RF00322_25, RF00322_17, RF00322_9, RF00322, RF00322_3, RF00322_22, RF00322_24, RF00322_13, RF00322_21, RF00322 4, RF00322 2, RF00322 12, RF00322 15, RF00322 20, RF00322 23,

[0961]

[0962] Table 17: markers only B list

[0963]

[0964] Table 18: markers in common between A2 and B lists

[0965]

[0966] Table 19: Number of Common genes between sets Cl C2 C3

[0967] C1 1149 436 156

[0968] C2 436 633 226

[0969] C3 156 226 370

[0970] Table 20: Cl list

[0971]

[0972] KIF9, KISS1R, KLF16, KLHL31, KLHL35, KLK10, KLK12, KPNA2, KRT18, KRT23, KRT80, LAGE3, LCN2, LDHA, LDLRAD3, LEMD1, LGR5, LIF, LINC01124, LIPG, LMNB2, 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, PLAU, PLCB1, PLEKHB1, PLEKHG4, PLK1, PLK4, PMAIP1, PMEPA1, PNMA5, POC1A, PODNL1, PODXL, POFUT1, POLA1, POLR1B, POLR1D, POLR3K, POM121C, POMP, PPA1, PPAT, PPIH, PPM1H, PRDX4, PRKDC, PROM1, PROSER1, 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,

[0973] 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

[0974] • 246 NOT protein coding genes with their names are:

[0975] AC004943.3, AC005062.1, AC005256.1,

[0976] 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,

[0977]

[0978] Table 21: C2 list

[0979]

[0980]

[0981] Table 22: C3 list

[0982]

[0983]

[0984] Table 23: Overlaps

[0985]

[0986]

[0987] AC009005.1, LINC01807, LINC01819,

[0988] LINC01594, AC090116.1, AP001042.1, AL 158064.1, AL 161431.1, AL590483.4, TRPM2-AS,

[0989] BOK-AS1, CASC19, LINC02253, LINC02254, LINC02086, DLGAP1-AS2, GAS6-AS1, LINC00858, LINC00920, PURPL, NPSR1-AS1, PLAC4, PROX1-AS1, AC093866.1,

[0990] 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

[0991] 226 common genes between C2 and C3 lists (144 protein coding genes and 82 NOT protein coding genes). In detail:

[0992] • 144 protein coding genes with their names are:

[0993] AGT, AL121761.1, APIP, ART3, ASCL2,

[0994] ASCL5, AXIN2, BACE2, BLACAT1, C17orf77, TEX45, LINC01555, LINC01549, C2CD4A, C2CD4B, C2orf70, CACNA2D2, CADPS, CCDC33, CCL20, CCNO, CDH3, CELSR3,

[0995] CHST4, CLCA1, CLDN2, CPNE7, CCDC192, CXCL1, CXCL3, CYP19A1, CYP4X1,

[0996] DACH1, DBNDD1, DLX6, DMRTA2, DSC3, DUOX2, DUSP27, EDAR, ENC1, EPHB2,

[0997] EPHB3, EPHX4, ETV4, IQANK1, FERMT1, FEZF1, FGFRL1, FZD9, GDF15, GGH,

[0998] 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,

[0999] NPFFR1, NPW, OLFM4, OXGR1, PCSK1, PDZK1IP1, PF4, PI3, PKD1L3, PLA2G4D,

[1000] PLCB4, PPM1H, PRKCG, PROX1, RAD51AP2, RAD54B, RAET1L, RASSF10, REG1A,

[1001] REG1B, REN, RETNLB, RNF183, RNF43, AC005833.1, AC027808.2, SALL4, SERPINA1, SH3TC2, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC5A8, SLC6A6, SLCO1B3,

[1002] SLCO5A1, SOX1, SOX9, SP5, SPINK4, TBX18, TCN1, TDGF1, TMEM211, TNFSF9,

[1003] TNS4, VWA2, WDR72, XKRX, ZNRF3

[1004] • 82 NOT protein coding genes with their names are:

[1005] AC002057.2, AC005307.1, FSIP2-AS2,

[1006] 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,

[1007] 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

[1008] 137 common genes between Cl, C2 and C3 lists

[1009] 137 common genes between Cl, C2 and C3 lists (93 protein coding genes and 44 NOT protein

[1010] coding genes). In detail:

[1011] • 93 protein coding genes with their names are:

[1012] 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,

[1013] MSX1, MSX2, NANOS3, NEBL, NKD1, NOTUM, NPFFR1, NPW, OLFM4, OXGR1,

[1014] PCSK1, PDZK1IP1, PI3, PPM1H, PROX1, RAD51AP2, RAET1L, REG1A, REG1B,

[1015] RNF183, RNF43, SALL4, SH3TC2, SLC12A2, SLC22A11, SLC28A3, SLC35D3, SLC6A6,

[1016] SOX1, SOX9, SP5, TDGF1, TNFSF9, TNS4, VWA2, WDR72, XKRX, ZNRF3

[1017]

[1018] Table 24: C4, C5, C6 lists and overlaps

[1019]

[1020] RILP, RMDN2, RNASEK, RNF152, RNPC3, ZNF236-DT, NPIPB12, IQCM, RPL10L, 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, SLC04C1, 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:

[1021] AC002398.1, AC002460.2, LINC01531,

[1022] 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, RNU6-611P, RNU6-657P, RNU6-668P, RNU6-762P, RNU6-890P, RNU6-969P, RNU7-119P, RNU7-40P, RNU7-41P, RNU7-45P, SNORA37, RF00406, RF00409, RF00090, SNORD89, SNORD96B

[1023] 329 genes from C5 list (197 protein coding genes and 132 NOT protein coding genes). In detail:

[1024] • 197 protein coding genes with their names are:

[1025] ABCA8, AC008397.1, SMIM32, ACOT1,

[1026] 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, CAI, CA2, CACNA2D2, CAMK2A, CAPN13, CCDC152, CCL25, CD163L1, CHMP4A, CIDEC, CKB, CLCA1, CLCA2, CLCA4, CLDN8, CNGA1, CNTN3, CNTN4, CNTNAP3B, C0L17A1, COL4A5, C0LCA1, CPM, CPS1, CPT1B, CWH43, DHRS9, DNASE1L3, DPF3, DU0X1, 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,

[1027] 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

[1028] • 132 NOT protein coding genes with their names are:

[1029] AC002511.2, AC004765.1, AC005307.1,

[1030] 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

[1031] 578 genes from C6 list. (187 protein coding genes and 391 NOT protein coding genes). In detail:

[1032] • 187 protein coding genes with their names are:

[1033] AC093323.3, AC110619.1, ADAM23,

[1034] 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, NEURODI, 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, EL0A2, TDRD1, TEKT3, TEX22, TGM4, TMEM63C, TMEM87B, TREE, TRIM58, TTC6, TTLL9, TYMS, UGT1A7, UGT1A1, USHBP1, USP44, WDR17, WSCD1, YJEFN3, ZNF385D, ZNF683, ZNF793, ZNF843, ZSCAN32

[1035] • 391 NOT protein coding genes with their names are:

[1036] AC002128.2, AC002460.2, LINC01531,

[1037] 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,

[1038] 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, AC...

Claims

CLAIMS:

1. A method for determining whether a subject is at risk of having a cancer comprising determining the level of at least one ncRNA in a biological sample obtained from the subject and wherein the expression level of the ncRNA correlates with the risk of having cancer and wherein the ncRNA is selected from Table A.

2. The method of claim 1 for predicting the risk of having a cancer that results from polygenic or multifactorial phenotypes.

3. The method of claim 1 for predicting the risk of having a colorectal cancer.

4. The method according to any one of claims 1 to 3 wherein the subject has at least one premalignant lesion.

5. The method according to any one of claims 1 to 4 wherein the biological sample is a tissue sample.

6. The method of claim 5 wherein the tissue sample is obtained from a premalignant lesion.

7. The method according to any one of claims 1 to 6 that further comprises comparing the expression level of the ncRNA with a predetermined reference value wherein detecting a difference between the expression level of the ncRNA and the predetermined reference value indicates whether the subject is or is not at risk of having cancer.

8. The method according to any one of claims 1 to 7 wherein a high level of the ncRNA indicates that the subject is at low risk of having a cancer, whereas a low level of the ncRNA indicates that the subject is at high risk of having a cancer.

9. The method according to any one of claims 1 to 8 that further comprises a step of determining the expression level of one or more additional immune markers in the biological sample obtained from the subject.

10. The method of claim 9 wherein the presence of main adaptive immune cell types in the biological sample is determined using 6-marker multiplex immunofluorescence: 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+).

11. The method of claim 9 wherein the functional status of T cells in the biological sample is determined using 8 marker multiplex IHC including T cells markers (CD3 and CD8), exhaustion markers (TIM3, PD1, PDL1, TCF1) and one proliferation marker (Ki67) in addition to cytokeratin.

12. The method of claim 9 wherein the presence of tertiary lymphoid structures (“TLS”) in the biological sample is determined using CD3 and CD20 staining. In some embodiments, the relative abundance and / or maturation of TLS is determined in the biological sample by determining the expression level of CD3, CD20, CD19, CXCR5, CD4, CD8, CD21, CD23, PD1, and Ki67.

13. The method of claim 9 that further comprises determining the expression levels of PDL1, CD3, CD20, CD19, CXCR5, CD4, CD8, PD1, Ki67, and TIM3.

14. The method of claim 9 that further comprises determining the expression levels of CD3 and CD 8.

15. The method according to any one of claims 1 to 14 wherein a score which is a composite of the expression levels of the different ncRNAs and optionally of one or more immune markers is determined and compared to the predetermined reference value wherein a difference between said score and said predetermined reference value is indicative whether the subject is at risk of having cancer.

16. The method according to any one of claims 1 to 15 that comprises a) quantifying the level of a plurality of ncRNAs and optionally one or more immune marker(s) in the biological sample; b) implementing an algorithm on data comprising the quantified plurality of ncRNAs and immune markers so as to obtain an algorithm output; c) determining the probability that the subject will develop a cancer from the algorithm output of step b).

17. A method for the prophylactic treatment of cancer in a subject having at least one premalignant lesion comprising administering to the subject a therapeutically effective amount of at least one chemopreventive agent wherein the subject has been considered as being at risk of having cancer by the predictive method according to any one of claims 1 to 16.

18. The method of claim 17 wherein the chemopreventive agent is an immune checkpoint inhibitor.

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