Patent Publication Number: US-2010112713-A1

Title: Methods For Detecting Colorectal Diseases And Disorders

Description:
STATEMENT OF GOVERNMENT SUPPORT 
     This invention was made in part with government support under grant number S06-039, from the National Institutes of Health. As such, the United States government has certain rights to the invention. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to methods and compositions for the detection of biomarkers associated with colorectal diseases and disorders. In preferred embodiments, said colorectal disease is colorectal cancer. In some embodiments, the invention relates to the detection of said biomarkers using non-invasive methods. In further embodiments, the invention relates to the isolation and evaluation of biomarkers residing in feces from a subject at risk for or exhibiting symptoms associated with a colorectal disease or disorder. In still further embodiments, said biomarkers include exfoliated colonocytes. In additional embodiments, messenger RNA (mRNA) transcripts isolated from said colonocytes and associated with said colorectal diseases and disorders are quantified. 
     BACKGROUND OF THE INVENTION 
     Diseases and disorders of the colon and rectum, collectively referred to as the colorectal region, affect millions of people worldwide. One of the most recognizable diseases, colorectal cancer, is among the most common forms of cancer and a leading cause of cancer-related death in the Western world. Current methods for detecting colorectal cancer and pre-cancerous lesions and polyps are based largely on the use of invasive, tube-based cameras known as colonoscopes or sigmoidoscopes. The use of such devices is often a source of anxiety and extreme discomfort for a patient. Therefore, the development and implementation of non-invasive methods and assays for detecting biomedical indicators or biomarkers associated with colorectal cancer holds great appeal. However, current non-invasive methods lack both the necessary sensitivity of the aforementioned invasive techniques and the capacity for detecting alterations in the expression of genes associated with colorectal cancer. Thus, there is a need for the development of non-invasive methods for determining colorectal diseases and disorders that further allows for the examination of a patient&#39;s colonic gene expression profile. 
     SUMMARY OF THE INVENTION 
     The present invention relates to methods and compositions for the detection of biomarkers associated with colorectal diseases and disorders. In preferred embodiments, said colorectal disease is colorectal cancer. In some embodiments, the invention relates to the detection of said biomarkers using non-invasive methods. In further embodiments, the invention relates to the isolation and evaluation of biomarkers residing in feces from a subject at risk for or exhibiting symptoms associated with a colorectal disease or disorder. In still further embodiments, said biomarkers include exfoliated colonocytes. In additional embodiments, mRNA transcripts isolated from said colonocytes and associated with said colorectal diseases and disorders are quantified. 
     In some embodiments, the invention relates to a method of detecting a biomarker associated with a colorectal disease or disorder comprising a) obtaining a fecal sample from a subject exhibiting symptoms associated with or at risk (e.g. at risk because of prior adenomas, at risk because of insulin resistance, at risk because of a history of adenomatous polyps, etc.) for said colorectal disease or disorder, b) isolating at least one biomarker from said fecal sample, and c) quantifying said biomarker. In further embodiments, said colorectal disease or disorder is selected from the group consisting of colorectal cancer, colon cancer, large bowel cancer, colonic polyps, anal cancer, general anal and rectal diseases, colitis, Crohn&#39;s disease, hemorrhoids, ischemic colitis, ulcerative colitis, diverticulosis, diverticulitis and irritable bowel syndrome. In still further embodiments, said fecal sample is obtained within two hours of excretion from said subject. In additional embodiments, said subject is a mammal. In some embodiments, said biomarker is messenger RNA. In further embodiments, said biomarker is associated with at least one gene. In still further embodiments, said gene is selected from the group consisting of ACADS, ADAM9, ALOX5, ALOX12B, ATOH1, AXIN2, BAX, BCL, BCL2L12, BECN, CEAL1, CDC42, CSPG2, CSPG4, CXCL-1, EGF, EGFR, F11R, FABP1, FOX, FOXD2, FOXD4L1, FOXL1, FOXL2, FOXP1, FOXP3, FOXD2, FOXO3A, GST-M4, GUCA2A, HMGCL, HOXA1, HOXA11, HOXB2, HOXB3, HOXD10, HSPA12B, ICAM1 (CD54), IGF2, IGFR-1, ITGB4BP, KAI1, KIT, MAPK11, MCM2, MUC5AC, NOX1, NPAT, OGG1, PCNA, PHB, PIK3R1, PIK3C2G, PLCG1, PLCG2, PLCD3, PLCD4, POLG, PRKACB, PTK2B, PTK2, SDC1, SPARC, TGFB2, TGFβ, TGM4, TIMP3, TNF, TNFRSF10B, UCP-3, WNT1, WNT3, Wnt3A, and Wnt5A. 
     In some embodiments, the invention relates to a method of measuring biomarker associated with a colorectal disease or disorder comprising a) obtaining a first fecal sample from a subject on a first diet, b) isolating mRNA from said fecal sample, c) determining a first mRNA profile, d) changing the diet of said subject to a second diet, f) obtaining a second fecal sample from a subject on said second diet, g) isolating mRNA from said fecal sample, h) determining a second mRNA profile, and j) comparing said first and second mRNA profiles. In further embodiments, said second mRNA profile indicates a reduced risk for developing adenomas. In still further embodiments, said second diet consists of consuming legumes. It is not intended that the present invention be limited by the precise nature of the diets employed. In one embodiment, a seven-day menu cycle is contemplated for the second diet with a standard set of legumes of the  Phaseolus vulgaris  species, such as, navy beans, pinto beans, and kidney beans in order to limit nutrient and phytochemical differences in the seven-day diet cycle. In further embodiments, the second diet contains at least 200 grams of legumes per day, more preferably approximately 250 grams of legumes per day. In still further embodiments, said second diet may be modified to provide other high glycemic index (GI) foods in the control or first diet such that the GI of the control or first diet has a GI of approximately 70 compared to a GI of 30 in the legume diet. In still further embodiments, said first diet and said second diet are controlled such that a constant level of energy available from dietary fat is maintained. In additional embodiments, the energy percentage of said dietary fat energy is at least 30%, more preferably between 32 and 33%. A further embodiment of the present invention is the use of a high legume, low glycemic index diet with a total dietary fiber intake of approximately 40 grams per day. In further embodiments, the invention relates to a corresponding high glycemic index diet comprising approximately 20 grams of total dietary fiber per day. A further embodiment of the present invention relates to the maintenance of the protein level of both the high glycemic index diet and the low glycemic index diet. In preferred embodiments, the energy percentage available from said protein level is at least 15%, preferably approximately 18%. It is further contemplated that said protein level is maintained through incorporation of protein sources including but in no way limited to red meat, fish and poultry. 
     In some embodiments, the present invention relates to a legume enriched, low glycemic index (GI), high fermentable fiber diet for reducing the risk of or symptoms associated with colorectal diseases and disorders in a subject. In further embodiments, said subject exhibits at least one risk factor. In still further embodiments, said risk factor includes but is in no way limited to insulin resistance and adenomatous polyps. In still further embodiments, at least one gene associated with a colorectal disease or disorder, and preferably at least two genes, are analyzed using the methods of the present invention. In additional embodiments, said gene or genes are analyzed for identifying subjects at risk for or exhibiting symptoms associated with risk factors including but not limited to adenomatous polyps and insulin resistance. 
     In some embodiments, the invention relates to a method of detecting a biomarker associated with a colorectal disease or disorder comprising a) obtaining a fecal sample from a subject exhibiting symptoms associated with or at risk (e.g. at risk because of prior adenomas, at risk because of insulin resistance, at risk because of a history of adenomatous polyps, etc.) for said colorectal disease or disorder, b) isolating at least one colonocyte from said fecal sample; c) further isolating at least one biomarker from said colonocyte, and d) quantifying said biomarker. In further embodiments, said colorectal disease or disorder is selected from the group consisting of colorectal cancer, colon cancer, large bowel cancer, colonic polyps, anal cancer, general anal and rectal diseases, colitis, Crohn&#39;s disease, hemorrhoids, ischemic colitis, ulcerative colitis, diverticulosis, diverticulitis and irritable bowel syndrome. In still further embodiments, said fecal sample is obtained within two hours of excretion from said subject. In additional embodiments, said subject is a mammal. In some embodiments, said biomarker is messenger RNA. 
     In some embodiments, the invention relates to a method of measuring biomarker associated with a colorectal disease or disorder comprising a) obtaining a first fecal sample from a subject on a first diet, b) isolating colonocytes from said first fecal sample; c) isolating mRNA from said colonocytes fecal samples; d) determining a first mRNA profile, e) changing the diet of said subject to a second diet, f) obtaining a second fecal sample from a subject on said second diet, g) isolating colonocytes from said second fecal sample; h) isolating mRNA from said colonocytes fecal samples; i) determining a second mRNA profile, and j) comparing said first and second mRNA profiles. In further embodiments, said second mRNA profile indicates a reduced risk for developing adenomas. In still further embodiments, said second diet consists of consuming only legumes. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures. 
         FIG. 1  shows a schematic overview of the experimental design as described in Example 1. 
         FIG. 2  shows the LDA classification (+IR, +Polyps)/class 0 (depicted as ◯), versus (−IR, −Polyps)/class 1 (Δ), at bl1 as described in Example 1. The concept of intrinsically multivariate predictive (IMP) genes is shown where expression profiles of a group of genes predict the phenotype. Results represent a linear classification of (+IR, +Polyps) subjects (◯) versus (−IR, −Polyps) subjects (Δ) at BL1. UCP2 and HOXA3 were used as individual one-feature sets (A and B) as compared with both genes together as a two-feature set (C). The bolstered error is 0.2784, 0.4882, and 0.1415 for (A), (B), and (C), respectively. 
         FIG. 3  shows the LDA classification (+IR, +Polyps)/class 0 (depicted as ◯), versus (−IR, −Polyps)/class 1 (Δ), at bl1 as described in Example 1. Effective classification of clinical phenotype or diet. (A), linear (LDA) classification of (+IR, +Polyps) subjects (◯) versus (−IR, −Polyps) subjects (Δ) at BL1; (B) linear (LDA) classification of (−IR, −Polyps) subjects on the control diet (◯) versus (−IR, −Polyps) subjects on the legume diet (Δ) using the crossover design and combining the microarrays from samples collected at the end of the two diet periods DP1 and DP2. 
         FIG. 4  shows the LDA classification (−IR, −Polyps, Control diet)/class 0 (depicted as ◯), versus (−IR, −Polyps, Legume diet)/class 1 (Δ) as described in Example 1. Potential design problems and importance of the experimental design factors IR and history of adenomas. (A) increased error in the LDA classification of (+IR, +Polyps) subjects (◯) versus (−IR, −Polyps) subjects (Δ) when both baselines BL1 and BL2 were included. (B) (+Polyps) subjects (◯) versus (−Polyps) subjects (Δ) at baselines BL1 and BL2. (C) (+IR) subjects (◯) versus (−IR) subjects (Δ) at all time points. 
         FIG. 5  shows the Housekeeping gene preparation. Two normalization issues were addressed. First, there was a large number of low-quality spots and second, while the microarray intensities showed no aberrant trend up to a certain point in time (relative to when microarray was performed), after a certain point there was a somewhat linear decline in intensity. Data points (blue dots) in  FIG. 5  show the average values of the 18 housekeeping genes across microarrays, ordered from earliest to latest with respect to the time of processing. Common good probes (2,584) across all 86 microarrays were identified. A good probe is defined as having, at most, two low measures across all 86 microarrays. Using a list of 575 housekeeping genes (16), 18 genes were identified from the 2,584 probes found in the previous step. Subsequently, the raw intensity of each of the 18 housekeeping genes was quantified, and those with missing values were excluded. As a result, there were a total of 18 housekeeping genes used for normalization in Example 1. Arrays were grouped across time and the average values of 18 housekeeping genes were calculated in  FIG. 5 . 
     
    
    
     Table I shows the classification groups, sample sizes and number of common genes in the set A 2   1 ∩B as described in Example 1. BL1 and BL2 indicate the base lines 1 or 2, +IR and −IR indicate present or absent insulin resistance, and +Polyps and −Polyps indicate presence or absence of polyps. 
     Table II shows the (+IR, +Polyps) data versus (−IR, −Polyps) data and BL1 as provided for in Example 1. Pair-wise or triplet-wise LDA classifiers are included when they rank higher than 20 th  in both lists. ε bolstered  denotes the bolstered re-substitution error for the respective classifier; Δε bolstered  denotes the largest increase in error for the feature set relative to all of its subsets and ε resub  denotes the re-substitution as described in Example 1. Shows the classification of (+IR, +Polyps) subjects versus (−IR, −Polyps) subjects at BL1. Single-gene, pair-wise, and triplet-wise LDA classifiers are shown. ε bolstered  denotes the bolstered resubstitution error for the respective classifier; Δε bolstered  denotes the largest decrease in error for the feature set relative to all of its subsets. 
     Table III shows the (−IR, −Polyps) on control versus (−IR, −Polyps) on legume diet as provided for in Example 1. Pair-wise or triplet-wise LDA classifiers are included when they rank higher than 30 th  in both lists. ε bolstered  denotes the bolstered re-substitution error for the respective classifier; Δε bolstered  denotes the largest increase in error for the feature set relative to all of its subsets and ε resub  denotes the re-substitution as described in Example 1. Shows the classification of (−IR, −Polyps) subjects on control diet versus (−IR, −Polyps) subjects on the legume diet. Single-gene, pair-wise, and triplet-wise LDA classifiers are shown. Refer to Table II for legend details. 
     Table IV shows the overall structure of the microarray data set. 
     Table V shows the Final classifier gene list. 
     Table VI A k   j ∩B represents the number of genes that are common between the set B of established colonic biomarkers and the spots A k   j  on the microarray set that passed quality threshold set by the parameters k and j. The value k=1.5 is the default value for the CodeLink image processing software, and j represents the number of accepted low (L) spots for a gene across all of the microarrays in the experiment. 
     Table VII shows the classification groups, sample size and number of common genes in each data set. BL1, baseline 1; BL2, baseline 2; +IR and IR indicate presence or absence of insulin resistance, respectively. +Polyps and −polyps indicate the presence or absence of polyps, respectively. 
     Table VIII shows Relative exfoliated cell gene expression levels in (+IR, +Polyps) vs (−IR, −Polyps) subjects at baseline 1 (BL1). Fold change represents the relative expression level in (+IR, +Polyps) subjects divided by (−IR, −Polyps) subjects for individual genes described in Table 1. p-values were computed using t-tests applied to the normalized data. 
     DEFINITIONS 
     To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims. 
     As used herein, “colorectal disease” and “colorectal disorder” refer to diseases and disorders of the colon, and rectum. While not limiting the scope of the invention in any way, colorectal diseases and disorders include but are in no way limited to colorectal cancer, colon cancer, large bowel cancer, colonic polyps, anal cancer, general anal and rectal diseases, colitis, Crohn&#39;s disease, hemorrhoids, ischemic colitis, ulcerative colitis, diverticulosis, diverticulitis and irritable bowel syndrome. 
     As used herein, “colorectal cancer”, also known as “colon cancer”, “large rectal cancer” and “anal cancer,” is a disease that originates from the epithelial cells lining the gastrointestinal tract. The disease is often characterized by the cancerous growths residing in the colon and/or rectum. Symptoms associated with colorectal cancer include but are in no way limited to change in bowel habits, change in the appearance of stool including but not limited to bloody stool, rectal bleeding, stool with mucus, and/or black tar-like stool, bowel obstruction, the presence of an abdominal tumor, unexplained weight loss, jaundice, abdominal pain, anemia and blood clots. 
     A “colonocyte” refers to an epithelial cell that lines the mammalian colon. 
     As used herein, a “biomarker” is a substance used as an indicator of a biomedical state. While not limiting the scope of the present invention in any way, it is often a characteristic that is objectively measured and evaluated as an indicator of normal biomedical processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker includes but is in no way limited to a nucleic acid sequence, peptide, protein, chemical modifier, chemical inhibitor, biomedical fluid or biomedical excrement. In preferred embodiments, the present invention relates to the detection and analysis of biomarkers associated with colorectal diseases and disorders. In even more preferred embodiments, said biomarker is messenger RNA. Examples of biomarkers associated with the detection of said colorectal diseases and disorders include but are in no way limited to biomarkers associated with ALOX12B (arachidonate 12-lipoxygenase), APC2 (adenomatous polyposis coli 2), Axin2 (conductin), BAD (bcl-2 antagonist of cell death), BECN1 (beclin 1), CA5B (carbonic anhydrase 5), CDC42 (G25K GTP-binding protein), CDK4 (cyclin-dependent kinase 4), CD44 (CD44 antigen), CSPG4 (chondroitin sulphate proteoglycan 4), CXCL-1 (chemokine CXC motif (GRO-alpha)), DAPK1 (death-associated protein kinase), EGF (epidermal growth factor), EGFR (epidermal growth factor receptor), FOXL1 (forkhead box protein L1), FOXL2 (forkhead box protein L2), FOXO1A (forkhead box protein O1A), FOXP3 (forkhead box protein P3), FOXP4 (forkhead box protein P4), FOXD2 (forkhead box protein D2), FOXO3A (forkhead box protein 3A), GST-M4 (glutathione S-transferase), GUCA2A (guanylate cyclase activator 2A), HOXA3 (homeobox gene A3), HOXB3 (homeobox gene B3), HOXC6 (homeobox gene C6), HOXD10 (homeobox gene D10), HSPA12B (heat shock protein A12B), ICAM1 (intracellular adhesion molecule 1 (CD54)), ID2 (inhibitor of DNA binding 2), IGF2 (insulin-like growth factor 2), IGFR-1 (insulin-like growth factor receptor 1), ITGB4BP (integrin beta 4 binding protein), KAI1 (CD82 tumor suppressor gene), KIT (proto-oncogen tyrosine-protein kinase), LEF-1 (lymphoid enhancer binding factor/T cell factor transcription factor), MAPK11 (mitogen activated protein kinase 11/p38 beta), MCM2 (minichromosome maintenance deficient 2), MUC5AC (secreted gel forming mucin 5AC), NOS3 (nitric oxide synthase 3), NOX1 (NADPH oxidase 1), NPAT (ataxia telangiectasia locus), OGG1 (8-oxoguanine DNA glycosylase), PCNA (proliferating cell nuclear antigen), PHB (prohibitin), PIK3R1 (phosphatidylinositol 3-kinase regulatory subunit p85 alpha), PIK3C2G (phosphoinositide 3-kinase, class 2, gamma polypeptide), PLCG2 (phosphatidylinositol-specific phospholipase gamma 2), PLCD4 (phospholipase C delta 4), POLG (DNA polymerase gamma), PRKACB (protein kinase, cyclic AMP-dependent, catalytic subunit beta), PTK2 (protein tyrosine kinase 2), SDC1 (syndecan 1), SFRP5 (secreted frizzled-related protein 5), SPARC, TGFβ (transforming growth factor beta 3), TNF (tumor necrosis factor), TNFRSF10B (tumor necrosis factor super family member 10B), TP53 (tumor suppressor protein p53), UCP-2 (uncoupling protein 2), UCP-3 (uncoupling protein 3), WNT1 (Wingless-type MMTV integration site family, member 1), Wnt3A (wingless-type MMTV integration site family member 3A), Wnt5A (wingless-type MMTV integration site family member 5A), YWHAZ (14-3-3 zeta). 
     As used herein, “energy percentage” is the percentage of energy, i.e. calories, derived from a macronutrient, including but in no way limited to carbohydrates, proteins and fats consumed by a subject. 
     As used herein, the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset of a disease or disorder. It is not intended that the present invention be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease or disorder is reduced. 
     As used herein, the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, the present invention also contemplates treatment that merely reduces symptoms, improves (to some degree) and/or delays disease progression. It is not intended that the present invention be limited to instances wherein a disease or affliction is cured. It is sufficient that symptoms are reduced. 
     “Subject” refers to any mammal, preferably a human patient, laboratory animal, livestock, or domestic pet. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to methods and compositions for the detection of biomarkers associated with colorectal diseases and disorders. In preferred embodiments, said colorectal disease is colorectal cancer. In some embodiments, the invention relates to the detection of said biomarkers using non-invasive methods. In further embodiments, the invention relates to the isolation and evaluation of biomarkers residing in feces from a subject at risk for or exhibiting symptoms associated with a colorectal disease or disorder. In still further embodiments, said biomarkers include exfoliated colonocytes. In additional embodiments, mRNA transcripts isolated from said colonocytes and associated with said colorectal diseases and disorders are quantified. 
     In preferred embodiments, the present invention relates to methods for the detection of colorectal diseases and disorders such as colorectal cancer. Early detection of colorectal cancer can greatly increase the prognosis for a subject exhibiting symptoms associated with the disease, thus it is desirable to have accurate screening methods and assays. Consistent with this goal, the adoption of non-invasive methodology designed to reduce anxiety over colorectal cancer screening and improve overall acceptance of the screening process would be highly desirable. Unfortunately, current non-invasive detection methods lack sensitivity and are incapable of detecting alterations in gene expression. This current limitation is significant because changes in gene expression can modulate the regulatory mechanisms that either promote or protect a subject against colorectal diseases and disorders such as colorectal cancer. Thus, the present invention utilizes a novel, non-invasive methodology based on the analysis of fecal or stool samples, which contain intact sloughed colon cells, in order to quantify colorectal disease and disorder relevant gene expression profiles. 
     Colon cancer is one of the leading causes of cancer-related deaths in the United States. Early detection is one of the proven strategies resulting in a higher cure rate (Rutter, 2006). Unfortunately, the currently adopted screening procedures for early detection are often invasive, e.g. colonoscopy, and discomfort associated with such procedures generally leads to resistance toward the screening process. Thus, adoption of noninvasive methodology designed to reduce anxiety over colorectal cancer screening and improve overall acceptance of the screening process would be highly desirable. See U.S. Pat. No. 6,258,541, hereby incorporated by reference. 
     Approximately one-sixth to one-third of normal adult colonic epithelial cells are shed daily as provided for in Potten (1979)  Biochimica et Biophysica Acta  560, 281-299, incorporated herein by reference. The present invention provides for novel, non-invasive methodologies utilizing feces, which contain exfoliated colonocytes, in order to quantify colonic mRNAs as provided for in Davidson et al. (1995)  Cancer Epidemiology Biomarkers and Prevention  4, 643-647; Davidson et al. (1998)  Carcinogenesis  19, 253-257; Davidson et al. (2003)  Biomarkers  8, 51-61, all of which are hereby incorporated by reference. Although RNA is generally less suitable than DNA because it is readily degraded, it has previously been demonstrated that intact fecal eukaryotic mRNA can be isolated because of the presence of viable exfoliated colonocytes in the fecal stream as described in Albaugh (1992)  International Journal of Cancer  52, 347-350; Davidson et al. (1995)  Cancer Epidemiology Biomarkers and Prevention  4, 643-647; Davidson et al. (2003)  Biomarkers  8, 51-61; Santiago et al. (2003)  Journal of Virology  77, 2233-2242 and Kanaoka et al. (2004)  Gastroenterology  127, 422-427, all of which are incorporated herein by reference. 
     Using exfoliated colonocytes, the discriminative mRNA expression signatures between conditions associated with inflammatory bowel disease versus normal conditions as well as conditions consistent with the presence of adenoma versus normal conditions has been described in Davidson et al. (2003)  Biomarkers  8, 51-61. Those data suggest that mRNA isolated from exfoliated human colonocytes can be used to detect early stages of colon cancer, and possibly chronic inflammation. However, the microarray gene expression profile-based classification of colonic diseases for diagnostic purposes has yet to be solved. Therefore, a further embodiment of the present invention is the utilization of non-invasive mRNA procedures in patients at high risk for colorectal adenoma recurrence. In some embodiments, the effect of a legume enriched, low glycemic index (GI), high fermentable fiber diet, on subjects exhibiting a combination of risk factors including insulin resistance and history of adenomatous polyps is evaluated. This method evaluates the effects of legumes or a low GI diet on changes in intestinal gene expression profiles using exfoliated colonocytes. A further embodiment of the present invention involves the implementation of diagnostic gene sets (combinations) analyses for the objective classification of different phenotypes. These methods allow for the identification of both individual genes and two- to three-gene combinations for distinguishing polyps, insulin resistance, and exposure to a legume diet. The disclosed methods further reduce the classification error rate, with two and three-gene combinations providing robust classifiers that non-invasively identify discriminative signatures for diagnostic purposes. 
     EXAMPLES 
     The following examples are provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. 
     In the experimental disclosure that follows, the following abbreviations apply: bl1 (base line 1); bl2 (base line 2); dp1 (diet period 1); dp2 (diet period 2); GI (glycemic index); IR (insulin resistance); mRNA (messenger RNA); RMR (resting metabolic rate). 
     Example I 
     Materials and Methods 
     The effects of a legume enriched, low glycemic index, high fermentable fiber diet, were evaluated in participants with four possible combinations of risk factors, including insulin resistance (IR) and a history of adenomatous polyps. In a randomized, crossover, design-controlled feeding study, each participant consumed the “experimental diet”, defined as 1.5 cups of cooked dry beans per day, as well as a “control diet”, defined as an isocaloric average American diet, for four weeks, with a three-week washout period between diets. A total of 68 male subjects were examined, with 17 males assigned to each of four groups: Group 1 (previous history of adenomas and IR); Group 2 (previous history of adenomas without IR); Group 3 (IR with no history of adenomas); and Group 4 (non-IR and no history of adenomas). The effects of patient risk and diet on global gene expression profiling were examined using exfoliated colonic cells collected from the male subjects. All procedures used in the study were reviewed and approved by the human subjects&#39; committees at the Pennsylvania State University and the National Institutes of Health. Study procedures are briefly summarized below. 
     Subject Recruitment 
     Subjects were recruited with the assistance of gastroenterologists performing colonoscopies at the Mount Nittany Medical Center in State College, Pa. After receiving informed consent, the subject&#39;s height, weight and blood pressure were checked by study staff or the nurses at the clinic and a fasting blood sample was taken to determine overall health including fasting insulin and glucose to determine insulin sensitivity and cholesterol levels and lab tests for heart and liver function. A physician reviewed the results to determine eligibility for participation, with eligible consented participants asked to return to assess their resting metabolic rate (RMR). Each participant completed demographic, health and lifestyle questionnaires and subsequently provided instructions for completing a four-day food record for the purpose of estimating pre-study, baseline dietary intake. 
     Inclusion and Exclusion Criteria 
     Eligible participants for the study were males between 35-75 years of age, with a body mass index of 25.0-34.9 kg/m 2 , and having previously undergone a screening colonoscopy within the past two years. Subjects were selected that lacked pre-existing medical conditions including but not limited to cancer, heart disease, kidney disease and diabetes as well as a family history of such conditions, including but not limited to colorectal cancer, surgical resection of adenomas, bowel resection, polyposis syndrome and inflammatory bowel disease. Subjects were not permitted to take any medication that would alter inflammation markers, insulin, glucose, or blood lipids. 
     Dietary Intervention 
     Subjects consumed one meal per day (breakfast or dinner) on site during the weekdays and consumed a packed lunch, snack and an additional meal at a time and place of convenience. Weekend meals were prepared and packed for carry out. Compliance was monitored according to procedures routinely used in the Pennsylvania State University General Clinical Center Research Center (GCRC). No foods other than those provided by the study kitchen were permitted. Alcohol consumption was limited to no more than two drinks/week during the controlled feeding period. A seven-day menu cycle was developed with a standard set of legumes of the Phaseolus vulgaris species, such as, navy beans, pinto beans, and kidney beans in order to limit nutrient and phytochemical differences in the seven-day diet cycle. The diet contained approximately 250 grams of legumes per day (1.5 cups). This level added approximately 20 grams of total dietary fiber and 8 g of soluble fiber/day. The diet was modified to provide other high glycemic index (GI) foods in the control diet so that the GI of the control diet had a GI of approximately 70 compared to a GI of 30 in the legume diet. Each daily menu was designed to maintain a constant level of fat (32-33 energy %), while the high legume low glycemic index diet had a total dietary fiber intake of approximately 40 grams per day compared to 20 grams per day for the high glycemic index diet. The protein level of both diets was approximately 18 energy %. In order to maintain the same level of red meat and fish (foods that have been associated with colon cancer) in both diets, the protein in legumes was substituted for protein from poultry. All nutrients were provided in amounts to meet the recommended dietary allowances for men of the same age groups. A food composite for each of the six days was freeze-dried and analyzed for macro-nutrient and fiber levels. Individual food items were purchased at the same time from the same supplier in order to assure uniformity of the diet. 
     mRNA Expression Microarray Analysis 
     The overall study design is shown in  FIG. 1 . All fecal samples were processed within two hours of excretion, coded by the Research Assistant and stored at −80 degrees C. at the Penn State GCRC for later analysis. From each subject, poly A + RNA was isolated from feces as disclosed in Davidson et al. (1995)  Cancer Epidemiology Biomarkers and Prevention  4, 643-647; Davidson et al. (1998)  Carcinogenesis  19, 253-257; Davidson et al. (2003)  Biomarkers  8, 51-61, all of which are hereby incorporated by reference. Due to the high level of bacterial RNA in fecal samples, poly A + RNA must be isolated in order to obtain a pure mammalian RNA population. As described in Davidson et al. (1995)  Cancer Epidemiology Biomarkers and Prevention  4, 643-647, the isolation of poly A +  is free of bacterial RNA contamination. In addition, an Agilent 2100 Bioanalyzer was used to assess integrity of mucosal and fecal poly A + RNA. Samples were processed in strict accordance to the CodeLink™ Gene Expression Assay manual (Applied Microarray, Tempe, Ariz.) and analyzed using the Human whole Genome Expression Bioarray as provided for in Davidson et al. (2004)  Cancer Research  64, 6797-6804, hereby incorporated by reference. Each array contains the entire human genome derived from publicly available, well-annotated mRNA sequences. This platform is unique because it is capable of detecting minimal differences in gene expression, as low as 1.3-fold with 95% confidence (Ramakrishnan, 2002; Stafford, 2003). The 3-D gel provides support for 30-mers in a matrix that holds the probe away from the surface of the slide. This substantially reduces background and enhances sensitivity, allowing for the detection of one transcript per cell with 50-200 ng of poly A + RNA (Stafford, 2003). 
     Arrays were inspected for spot morphology. Marginal spots were flagged as either background contamination (C) or irregular shape (I) in the output of the scanning software. Spots that passed the quality control standards were categorized as good (G). In addition, spots marked with (L) indicated a corresponding reading was “near the background”. The low (L) measurements reflect either true low gene expression levels or may have been caused by degradation of the mRNA resulting in a low signal. Samples collected from colonic mucosa previously exhibited a relatively low proportion (5-8%) of L spots as disclosed in Davidson et al. (2004)  Cancer Research  64, 6797-6804, incorporated herein by reference. In contrast, the proportion of L spots in data obtained from fecal samples was significantly higher (65-83%). 
     Microarray Data Normalization 
     The standard procedure for microarray data analysis requires a normalization step to facilitate the comparison of gene expression levels from two or more arrays. The goal of such a processing step is to reduce the technical variance while preserving the biologically meaningful variance produced by the different experimental conditions/treatments. The normalization procedures can be either “local” or “global” as disclosed in Quackenbush (2002)  Nature Genetics Supplement  32, 496-501, incorporated in its entirety by reference. Besides these, model-based, parametric or non-parametric normalization procedures have been disclosed in Kerr et al. (2001)  Genetic Research  77, 123-128; Sidorov et al. (2002)  Information Sciences  146, 65-71; Bolstad et al. (2003)  Bioinformatics  19, 185-193, all of which are incorporated herein by reference. However, none of these methods were developed for the situations where one deals with a high percentage of partially degraded mRNA in the samples. Recently, we proposed a two-stage normalization procedure for such data sets as described in Liu et al. (2005)  Bioinformatics  21, 4000-4006, incorporated herein by reference. The method is built on non-parametric smoothing techniques with robustness consideration, and was used to evaluate the feasibility of properly extracting information from fecal mRNA data. We note, that the main objective of the two-stage normalization is to “regularize” the G spots for each gene while including the L spots that behave “similarly” to other G probes for that same gene, and excluding the outlying G probes. In contrast, our goal was to identify groups of genes/features that distinguish or classify between the different combinations of risk factors. Therefore, we adopted a conservative approach that does not include a normalization step, and focuses on a subset of genes that have been implicated in colorectal carcinogenesis. This procedure is justified by the observation that applying any kind of normalization to a data set with a high percentage of L spots has the potential to “flatten” the signal that results in a loss of data. 
     Developing an Algorithm for Identifying Feature (Gene) Sets 
     Because there is high percentage of L spots on each array in the data set we first examined how the values of the parameters used by the CodeLink scanning software affect the number of G spots that are common for a subset of the arrays in our data set. To be specific, denoted by A k   j  the set of genes x i  that have at most j raw mean spot intensity values less than where μ i,l +kσ i,l  where μ i,l  is the value of local background median for the spot representing the gene x i  on the lth array, and σ i,l  is the corresponding standard deviation for that background signal. For example A 1.5   0  is the set of G spots that are common for all of the arrays in the data set (by default k=1.5 in the CodeLink software). Spots that are flagged C are not considered when the sets A k   j  are formed. Notice that A k   j   ⊂ A s   r  if s≦k and j≦r. In particular, A k   j   ⊂ A s   j , s≦k represents the fact that one gets a lesser number of common good spots if one requires a stronger signal as compared to the background. Also, A k   j   ⊂ A k   r , j≦r represents the fact that the number of common genes increases if one allows more L spots per gene. 
     Keeping in mind that our main goal is to check if mRNA data from fecal colonocytes has the potential to classify different colon cancer risk factors we combined the so obtained sets A k   j  with a set B of approximately 1300 known human colonic markers. Because our main goal was to determine if mRNA data from exfoliated colonocytes have the potential to classify different colon cancer risk factors, we compared the obtained array data sets (termed A) with a set of 529 putative human colonic markers (termed B; refer to Table V). Using such a prior biological knowledge we investigated the sets of common genes for A k   j  and B. The number of those common genes for various values of the parameters k and j are given in Table VI. Based on these results, we focus on the intersection A 2   1 ∩B. This conservative approach provides us with a subset of the known colonic biomarkers that have strong signal (k=2 compare to the CodeLink weaker default condition k=1.5) and no more than 1 low signal spot on the entire data set. One should notice that the microarray data could be grouped into various combinations of two different classes. This is due to the experimental design which lists to risk factors: (IR), and (−IR); four time points: Base line 1 (bl1), Diet period 1 (dp1), Base line 2 (bl2), Diet period 2 (dp2); and two diets: high legume low glycemic index, and control. These different groupings produce their respective sets A k   j  that could be larger or smaller depending on which of the microarrays are included in the corresponding groups and classes (Table VII). Obviously, A k   j  has the smallest possible size when one considers all of the data as being divided into two major categories, e.g. (+IR) vs (−IR). The next step in finding feature sets is to design classifiers that categorize samples based on the expression values of the genes from the intersection A 2   1 ∩B. An important consideration is that the number of genes in such gene feature sets should be sufficiently small, and we construct the classifiers for feature sets of size 1, 2, and 3. There are two reasons why we desire classifiers involving small numbers of genes: (a) the limited number of samples often available in clinical studies makes classifier design and error estimation problematic for large feature sets as provided for in Dougherty et al. (2001)  Comparative and Functional Genomics  2, 28-34, incorporated herein by reference, and (b) small gene sets facilitate design of practical immunohistochemical diagnostic panels. Thus, we use a simple linear discriminant analysis (LDA) classifier and a small number of genes. Given a set of features on which to base a classifier, one has to address not only the classifier design from sample data, but also the estimation of its error. When the number of potential feature sets is large, the key issue is whether a particular feature set provides good classification. A key concern is the precision with which the error of the designed classifier estimates the error of the optimal classifier. When data are limited, an error estimator may have a large variance and therefore may often be low. This can produce many feature sets and classifiers with low error estimates. The algorithm we use mitigates this problem by applying the bolstered error estimation as disclosed in Braga-Neto et al. (2004)  Pattern Recognition  37, 1267-1281, incorporated in its entirety by reference. It has advantages with respect to commonly used error estimators such as re-substitution, cross-validation, and bootstrap methods for error estimation in terms of speed and accuracy (bias and variance). The basic idea is to bolster the original empirical distribution of the available data by means of suitable bolstering kernels placed at each datapoint location. The error can be computed analytically in some cases, such as in the case of LDA. The relatively small size of the set A 2   1 ∩B allows for a comparing the errors of the potential feature sets of size 1, 2, and 3. The results of those comparisons are discussed in the next section. 
     Results and Discussion 
     Classification Analysis 
     In this feasibility study, our aim was to develop mRNA expression patterns that may establish the basis of a new non-invasive molecular diagnostic method. For this purpose, we applied an algorithm to 12 different pairs of classes arising from the experimental design as described in  FIG. 1 . The number of genes/features for each linear classifier was limited to three, which allowed for an exhaustive search. Biologists are often interested in finding individual genes that have some influence on the system under study. In the context of classification, this approach translates into finding single-gene classifiers. To illustrate how our approach compares to the traditional statistical analysis, we considered the classes (+IR, +Polyps) vs (−IR, −Polyps) at bl1. The top 10 feature sets of size 1 were compared to the differentially expressed genes in the set A 2   1 ∩B, where t-tests were performed using the log 2 -transformed raw intensity values. The comparison revealed that 7 out of the 10 top 1-feature sets (genes) identified by the linear (LDA) classifier also had p-values &lt;0.05. This should not be surprising because individual, differentially expressed genes are often used to discriminate between phenotypes. The results disclosed herein show that there are several cases where single genes can provide good classification in terms of the error estimate. However, when comparing these results to the two-feature classification for the same two classes, a trend is observed as described in Martins et al. (2008)  Journal of Selected Topics in Signal Processing  2, 424-439, incorporated in relevant parts by reference. The concept of intrinsically multivariate predictive (IMP) genes was introduced based on observations where expression profiles of a group of genes predicts the target, e.g. a gene or a phenotype) with great accuracy while any proper subset of these genes produces poor prediction. 
     The concept of intrinsically multivariate predictive (IMP) genes is shown where expression profiles of a group of genes predict the phenotype. Results represent a linear classification of (+IR, +Polyps) subjects (◯) versus (−IR, −Polyps) subjects (Δ) at BL1. UCP2 and HOXA3 were used as individual one-feature sets (A and B) as compared with both genes together as a two-feature set (C). The bolstered error is 0.2784, 0.4882, and 0.1415 for (A), (B), and (C), respectively. Specifically, the expression profiles of a group of genes predicted the target (either a gene or a phenotype) with greater accuracy relative to any proper subset of these genes. For example, single-gene classifiers (one-feature) based on either the Homeoboxpr otein-A3 (HOXA3) or uncoupling protein-2 (UCP2) performed very poorly when discriminating between (+IR, +Polyps) and (−IR, −Polyps) at BL1 (Table II;  FIGS. 2A  and B). Interestingly, HOXA3 was close to the worst predictor of all of the available 97 genes (ranked 94). In comparison, when combined as a two-feature set, UCP2 and HOXA3 provided one of the best two-feature classifiers (one misclassified data point only) among all of the 4,656 possible two-gene sets (Table II; 3C). These data clearly illustrate why complex phenotypes can be explained better by multivariate feature sets. 
     To identify sets of genes that perform in a multivariate manner to provide strong classification, we specifically looked for pairs of genes that performed better than either of the genes individually, and triplets of genes that performed well and substantially better than the best-performing pair among the three, and so on. To estimate the improvements of the classification performance, we introduced two quantities for each feature set: ε bolstered  and Δ(ε bolstered ). ε bolstered  denotes the bolstered resubstitution error for the LDA classifier for the respective feature set, and Δ(ε bolstered ) denotes the largest decrease in error for the full feature set relative to all of its subsets. The feature sets were initially ranked based on the value of ε bolstered , and subsequently ranked again based on the improvement Δ(ε bolstered ). For multiple-gene classifiers, we focused on feature sets with high rank in both lists. Along these lines, we designed two-feature classifiers for the classification of (+IR, +Polyps) versus (−IR, −Polyps) data at baseline BL1; (−IR, −Polyps, control diet) versus (−IR, −Polyps, legume diet) data at the end of the two diet periods DP1 and DP2; (+IR, +Polyps) versus (−IR, −Polyps) at baselines BL1 and BL2; (+Polyps) versus (−Polyps) at baselines BL1 and BL2; and (+IR) versus (−IR) at all of the time points. Table II and Table III describe the best (according to this ranking procedure) feature sets identified for the first two of these classification categories, and  FIGS. 3A  and B shows representative multivariate classifiers. 
     The results in  FIG. 4  show that the two factors, IR and history of adenomas, should be considered in tandem when determining the risk for the patient. For example, combining baseline samples (BL1 and BL2) increased the classification error, indicating complications related to the crossover design ( FIG. 4A ). Similarly, the three-feature set LDA classifiers performed poorly when the classification was considered separately with respect to either one of the two experimental factors (IR) or (Polyps;  FIGS. 4B  and C). The advantage of reporting the results in this way is that multivariate discriminatory power is revealed. This is clearly shown in Table II with regard to HOXA3. The gene did not appear on the single-gene list, indicating that the error of the respective classifier exceeded 0.3 (εbolstered=0.4882). However, it appeared with UCP2, 14-3-3ζ (YWHAZ), insulin growth factor receptor-I (IGF1R), beclin-1 (BECN1), and mitogen-activated protein kinase-11 (MAPK11) genes in the two-gene and three-gene lists, which improved classification error. Interestingly, members of the homeoprotein family of transcription factors (HOXA3 and HOXC6) are developmental regulators of gastrointestinal growth, patterning, and differentiation (Fujiki K, Duerr E, Kikuchi H, et al. Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth. Gastroenterology 2008; 135:907-16). It is also noteworthy that YWHAZ and IGF1R are capable of regulating apoptosis and cell adhesion (Sekharam M, Zhao H, Sun M, et al. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-xL pathway. Cancer Res 2003; 63:7708-16, Niemantsverdriet M, Wagner K, Visser M, Backendorf C. Cellular functions of 14-3-3ζ in apoptosis and cell adhesion emphasize its oncogenic character. Oncogene 2008; 27:1315-9); UCP2 promotes chemoresistance in cancer cells and mitochondrial Ca2+ sequestration; BECN1 stimulates autophagy and inhibits tumor cell growth (Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 2008; 90:313-23); and MAPK11 (p38β) mediates response to inflammatory cytokines and cellular stress (Beardmore V A, Hinton H J, Eftychi C, et al. Generation and characterization of p38β (MAPK11) gene-targeted mice.  Mol Cell Biol  2005; 25:10454-64). For comparative purposes, fold changes in select genes are presented in Table VIII. 
     
       
         
           
               
               
               
             
               
                 TABLE I 
               
               
                   
               
               
                   
                 Sample 
                 Common Genes 
               
               
                 Classification Groups 
                 Size 
                 in A 1   2  ∩C 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 (+IR, +Polyps) VS (−IR, −Polyps) at BL1 
                 12 
                 97 
               
               
                 (+IR, +Polyps) on Control VS (+IR, +Polyps) on Legume 
                 11 
                 103 
               
               
                 (−IR, −Polyps) on Control VS (−IR, −Polyps) on Legume 
                 12 
                 145 
               
               
                 (+IR, +Polyps) on Control VS (−IR, −Polyps) on Control 
                 11 
                 121 
               
               
                 (+IR, +Polyps) on Legume VS (−IR, −Polyps) on Legume 
                 12 
                 114 
               
               
                 (+IR, +Polyps) VS (−IR, −Polyps) at BL1 &amp; BL2 
                 21 
                 92 
               
               
                 (+Polyps) VS (−Polyps) at BL1 
                 23 
                 64 
               
               
                 (+IR) VS (−IR) at BL1 
                 23 
                 64 
               
               
                 (+Polyps) VS (−Polyps) at BL1 &amp; BL2 
                 41 
                 59 
               
               
                 (+Polyps) on Control VS (+Polyps) on Legume 
                 21 
                 87 
               
               
                 (+IR) on Control VS (+IR) on Legume 
                 23 
                 74 
               
               
                 (+IR) VS (−IR) at all time points 
                 86 
                 54 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE II 
               
               
                   
                   
               
               
                   
                 Gene names 
                 ε bolstered   
                 Δ(ε bolstered ) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 IGF1R 
                 0.1094 
                   
               
               
                   
                 CDK4 
                 0.1200 
               
               
                   
                 BECN1 
                 0.1223 
               
               
                   
                 NOS3 
                 0.1436 
               
               
                   
                 ALOX12B 
                 0.1477 
               
               
                   
                 NOS3, WNT1 
                 0.1277 
                 0.2656 
               
               
                   
                 HOXA3, UCP2 
                 0.1415 
                 0.3467 
               
               
                   
                 IGF1R, WNT1 
                 0.1484 
                 0.2449 
               
               
                   
                 ID2, IGF1R 
                 0.1486 
                 0.3139 
               
               
                   
                 HOXA3, YWHAZ 
                 0.1503 
                 0.3379 
               
               
                   
                 HOXA3, IGF1R 
                 0.1513 
                 0.3369 
               
               
                   
                 BECN1, HOXA3, MAPK11 
                 0.0891 
                 0.3991 
               
               
                   
                 BECN1, HOXA3, IGF1R 
                 0.0907 
                 0.3975 
               
               
                   
                 HOXA3, MAPK11, YWHAZ 
                 0.0935 
                 0.3947 
               
               
                   
                 HOXA3, HOXC6, MAPK11 
                 0.0941 
                 0.3941 
               
               
                   
                 HOXA3, MAPK11, NOS3 
                 0.0987 
                 0.3895 
               
               
                   
                 HOXA3, UCP2, YWHAZ 
                 0.1001 
                 0.3881 
               
               
                   
                 HOXA3, IGF1R, YWHAZ 
                 0.1006 
                 0.3876 
               
               
                   
                 BECN1, DAPK1, IGF1R 
                 0.1012 
                 0.3768 
               
               
                   
                 HOXA3, HOXC6, TJP1 
                 0.1023 
                 0.3859 
               
               
                   
                 HOXA3, HOXC6, IGF1R 
                 0.1079 
                 0.3803 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE III 
               
               
                   
                   
               
               
                   
                 Gene names 
                 ε bolstered   
                 Δ(ε bolstered ) 
               
               
                   
                   
               
             
            
               
                   
                 TGFB3 
                 0.2350 
                   
               
               
                   
                 FOXP4 
                 0.2586 
               
               
                   
                 TP53 
                 0.2970 
               
               
                   
                 BAD 
                 0.3009 
               
               
                   
                 FOXO1A 
                 0.3033 
               
               
                   
                 DAPK1, HOXA3 
                 0.1829 
                 0.3760 
               
               
                   
                 BAD, LYZL6 
                 0.2275 
                 0.2321 
               
               
                   
                 IGF1R, LEF1 
                 0.2315 
                 0.2488 
               
               
                   
                 DAPK1, FOXM1 
                 0.2371 
                 0.2336 
               
               
                   
                 IGF2, TGFB3 
                 0.2455 
                 0.2814 
               
               
                   
                 LEF1, TGFB3 
                 0.2459 
                 0.2344 
               
               
                   
                 DAPK1, TP53 
                 0.2642 
                 0.2426 
               
               
                   
                 APC, CDC42 
                 0.2650 
                 0.2564 
               
               
                   
                 DAPK1, HOXA3, TGFB3 
                 0.1675 
                 0.3914 
               
               
                   
                 DAPK1, LEF1, TGFB3 
                 0.1799 
                 0.3004 
               
               
                   
                 DAPK1, HOXA3, LEF1 
                 0.1854 
                 0.3735 
               
               
                   
                 DAPK1, HOXA3, SELP 
                 0.1887 
                 0.3702 
               
               
                   
                 CAMK2A, DAPK1, HOXA3 
                 0.1922 
                 0.3667 
               
               
                   
                 DAPK1, HOXA3, SPARC 
                 0.1944 
                 0.3645 
               
               
                   
                 DAPK1, HOXA3, PRKACG 
                 0.1969 
                 0.3620 
               
               
                   
                 DAPK1, HOXA3, SFRP5 
                 0.1982 
                 0.3607 
               
               
                   
                 BAD, FOXE3, PTK2 
                 0.2003 
                 0.3018 
               
               
                   
                 CA5B, DAPK1, HOXA3 
                 0.2028 
                 0.3561 
               
               
                   
                 CD44, DAPK1, HOXA3 
                 0.2052 
                 0.3537 
               
               
                   
                 BAD, FOXP4, GSS 
                 0.2056 
                 0.3112 
               
               
                   
                 BAD, FOXE3, PTK2B 
                 0.2072 
                 0.3187 
               
               
                   
                 APC2, DAPK1, HOXA3 
                 0.2117 
                 0.3472 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                 TABLE IV 
               
               
                   
               
               
                 Subject ID 
                 Study Group 
                 BL 1 
                 End DP 1 
                 BL 2 
                 End DP 2 
                 Subject ID 
                 DP1 
                 DP2 
               
               
                   
               
             
            
               
                 LEG 01 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 01 
                 L 
                 C 
               
               
                 LEG 02 
                 2 
                 x 
                 x 
                 x 
                 x 
                 LEG 02 
                 C 
                 L 
               
               
                 LEG 03 
                 1 
                 x 
                 x 
                 x 
                 x 
                 LEG 03 
                 C 
                 L 
               
               
                 LEG 04 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 04 
                 L 
                 C 
               
               
                 LEG 05 
                 2 
                 x 
                 x 
                 x 
                 x 
                 LEG 05 
                 L 
                 C 
               
               
                 LEG 06 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 06 
                 C 
                 L 
               
               
                 LEG 08 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 08 
                 C 
                 L 
               
               
                 LEG 09 
                 2 
                 x 
                 x 
                 x 
                 x 
                 LEG 09 
                 L 
                 C 
               
               
                 LEG 10 
                 2 
                 x 
                 x 
                 m 
                 x 
                 LEG 10 
                 C 
                 L 
               
               
                 LEG 11 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 11 
                 L 
                 C 
               
               
                 LEG 13 
                 1 
                 x 
                 x 
                 m 
                 x 
                 LEG 13 
                 C 
                 L 
               
               
                 LEG 14 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 14 
                 C 
                 L 
               
               
                 LEG 18 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 18 
                 L 
                 C 
               
               
                 LEG 19 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 19 
                 C 
                 L 
               
               
                 LEG 24 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 24 
                 L 
                 C 
               
               
                 LEG 26 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 26 
                 C 
                 L 
               
               
                 LEG 27 
                 4 
                 x 
                 x 
                 x 
                 x 
                 LEG 27 
                 L 
                 C 
               
               
                 LEG 33 
                 2 
                 x 
                 x 
                 m 
                 x 
                 LEG 33 
                 C 
                 L 
               
               
                 LEG 44 
                 1 
                 x 
                 x 
                 m 
                 x 
                 LEG 44 
                 L 
                 C 
               
               
                 LEG 47 
                 1 
                 x 
                 x 
                 x 
                 x 
                 LEG 47 
                 C 
                 L 
               
               
                 LEG 49 
                 1 
                 x 
                 x 
                 m 
                 x 
                 LEG 49 
                 L 
                 C 
               
               
                 LEG 54 
                 1 
                 x 
                 x 
                 x 
                 m 
                 LEG 54 
                 L 
                 C 
               
               
                 LEG 65 
                 3 
                 x 
                 x 
                 x 
                 x 
                 LEG 65 
                 C 
                 L 
               
               
                   
               
               
                 x = array was processed; 
               
               
                 m = missing sample 
               
               
                 L = Legume diet: 
               
               
                 C = American control diet 
               
               
                 Study Group: 
               
               
                 1 = +insulin resistance/+polyps; 
               
               
                 2 = −insulin resistance/+polyps 
               
               
                 3 = +insulin resistance/−polyps: 
               
               
                 4 = −insulin resistance/−polyps 
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE V 
               
               
                   
                   
               
               
                   
                   
                   
                 Gene 
               
               
                   
                 PROBE_NAME 
                 NCBI_ACC 
                 abbreviation 
               
               
                   
                   
               
             
            
               
                   
                 GE55294 
                 NM_012138.2 
                 AATF 
               
               
                   
                 GE57835 
                 NM_000927.3 
                 ABCB1 
               
               
                   
                 GE82449 
                 NM_018849.1 
                 ABCB4 
               
               
                   
                 GE60435 
                 NM_000017.1 
                 ACADS 
               
               
                   
                 GE54239 
                 NM_004458.1 
                 ACSL4 
               
               
                   
                 GE59148 
                 NM_003816.2 
                 ADAM9 
               
               
                   
                 GE53921 
                 NM_006988.3 
                 ADAMTS1 
               
               
                   
                 GE61341 
                 NM_005099.3 
                 ADAMTS4 
               
               
                   
                 GE80938 
                 NM_000697.1 
                 ALOX12 
               
               
                   
                 GE54325 
                 NM_001139.1 
                 ALOX12B 
               
               
                   
                 GE80985 
                 NM_001140.3 
                 ALOX15 
               
               
                   
                 GE59425 
                 NM_001141.1 
                 ALOX15B 
               
               
                   
                 GE57484 
                 NM_000698.1 
                 ALOX5 
               
               
                   
                 GE54404 
                 NM_005503.2 
                 APBA2 
               
               
                   
                 GE58061 
                 NM_000038.3 
                 APC 
               
               
                   
                 GE53318 
                 NM_005883.1 
                 APC2 
               
               
                   
                 GE58776 
                 NM_001641.2 
                 APEX1 
               
               
                   
                 GE59705 
                 NM_000045.2 
                 ARG1 
               
               
                   
                 GE59481 
                 NM_001172.3 
                 ARG2 
               
               
                   
                 GE62666 
                 NM_005172.1 
                 ATOH1 
               
               
                   
                 GE57035 
                 NM_001686.3 
                 ATP5B 
               
               
                   
                 GE53329 
                 NM_006095.1 
                 ATP8A1 
               
               
                   
                 GE61790 
                 NM_003502.2 
                 AXIN1 
               
               
                   
                 GE58341 
                 NM_004655.1 
                 AXIN2 
               
               
                   
                 GE61740 
                 NM_032989.1 
                 BAD 
               
               
                   
                 GE60444 
                 NM_001188.2 
                 BAK1 
               
               
                   
                 GE57679 
                 NM_004324.3 
                 BAX 
               
               
                   
                 GE79818 
                 NM_003921.2 
                 BCL10 
               
               
                   
                 GE62993 
                 NM_004049.2 
                 BCL2A1 
               
               
                   
                 GE60374 
                 NM_138578.1 
                 BCL2L1 
               
               
                   
                 GE80623 
                 NM_020396.2 
                 BCL2L10 
               
               
                   
                 GE890567 
                 NM_138622.2 
                 BCL2L11 
               
               
                   
                 GE83665 
                 NM_138639.1 
                 BCL2L12 
               
               
                   
                 GE61161 
                 NM_015367.2 
                 BCL2L13 
               
               
                   
                 GE83170 
                 NM_030766.1 
                 BCL2L14 
               
               
                   
                 GE57412 
                 NM_004050.2 
                 BCL2L2 
               
               
                   
                 GE79828 
                 NM_003766.2 
                 BECN1 
               
               
                   
                 GE59117 
                 NM_001166.3 
                 BIRC2 
               
               
                   
                 GE612545 
                 AI873224.1 
                 BIRC4 
               
               
                   
                 GE59394 
                 NM_001168.1 
                 BIRC5 
               
               
                   
                 GE57870 
                 NM_001200.1 
                 BMP2 
               
               
                   
                 GE59170 
                 NM_001202.2 
                 BMP4 
               
               
                   
                 GE55306 
                 NM_017589.2 
                 BTG4 
               
               
                   
                 GE58358 
                 NM_005181.2 
                 CA3 
               
               
                   
                 GE58106 
                 NM_000717.2 
                 CA4 
               
               
                   
                 GE58264 
                 NM_001739.1 
                 CA5A 
               
               
                   
                 GE53590 
                 NM_007220.2 
                 CA5B 
               
               
                   
                 GE53630 
                 NM_015981.2 
                 CAMK2A 
               
               
                   
                 GE62184 
                 NM_001221.2 
                 CAMK2D 
               
               
                   
                 GE58946 
                 NM_032991.1 
                 CASP3 
               
               
                   
                 GE61602 
                 NM_001752.1 
                 CAT 
               
               
                   
                 GE54670 
                 NM_001753.3 
                 CAV1 
               
               
                   
                 GE57886 
                 NM_031966.2 
                 CCNB1 
               
               
                   
                 GE795552 
                 AW439398.1 
                 CCND1 
               
               
                   
                 GE79118 
                 NM_013230.1 
                 CD24 
               
               
                   
                 GE59805 
                 NM_001001389.1 
                 CD44 
               
               
                   
                 GE62023 
                 NM_212530.1 
                 CDC25B 
               
               
                   
                 GE57603 
                 NM_001791.2 
                 CDC42 
               
               
                   
                 GE57732 
                 NM_004360.2 
                 CDH1 
               
               
                   
                 GE59262 
                 NM_001257.2 
                 CDH13 
               
               
                   
                 GE54070 
                 NM_004642.2 
                 CDK2AP1 
               
               
                   
                 GE57828 
                 NM_000075.2 
                 CDK4 
               
               
                   
                 GE58861 
                 NM_000389.2 
                 CDKN1A 
               
               
                   
                 GE81344 
                 NM_004064.2 
                 CDKN1B 
               
               
                   
                 GE80886 
                 NM_000076.1 
                 CDKN1C 
               
               
                   
                 GE59038 
                 NM_058195.2 
                 CDKN2A 
               
               
                   
                 GE81459 
                 L36844.1 
                 CDKN2B 
               
               
                   
                 GE79397 
                 NM_001804.1 
                 CDX1 
               
               
                   
                 GE59216 
                 NM_001265.2 
                 CDX2 
               
               
                   
                 GE59735 
                 NM_001712.2 
                 CEACAM1 
               
               
                   
                 GE62998 
                 NM_001815.1 
                 CEACAM3 
               
               
                   
                 GE81072 
                 NM_001817.1 
                 CEACAM4 
               
               
                   
                 GE81388 
                 NM_004363.1 
                 CEACAM5 
               
               
                   
                 GE79541 
                 NM_002483.3 
                 CEACAM6 
               
               
                   
                 GE54005 
                 NM_006890.1 
                 CEACAM7 
               
               
                   
                 GE579012 
                 NM_001816.2 
                 CEACAM8 
               
               
                   
                 GE87279 
                 NM_020219.2 
                 CEAL1 
               
               
                   
                 GE742535 
                 NM_033377.1 
                 CGB1 
               
               
                   
                 GE62911 
                 NM_033142.1 
                 CGB7 
               
               
                   
                 GE54896 
                 AY358652.1 
                 CLDN1 
               
               
                   
                 GE79293 
                 NM_001306.2 
                 CLDN3 
               
               
                   
                 GE54025 
                 NM_003277.2 
                 CLDN5 
               
               
                   
                 GE56220 
                 NM_199328.1 
                 CLDN8 
               
               
                   
                 GE54150 
                 NM_130444.1 
                 COL18A1 
               
               
                   
                 GE80889 
                 NM_000089.3 
                 COL1A2 
               
               
                   
                 GE59553 
                 NM_001861.2 
                 COX4I1 
               
               
                   
                 GE81079 
                 NM_001862.2 
                 COX5B 
               
               
                   
                 GE61834 
                 NM_015513.2 
                 CRELD1 
               
               
                   
                 GE61173 
                 NM_004385.2 
                 CSPG2 
               
               
                   
                 GE54206 
                 NM_004386.1 
                 CSPG3 
               
               
                   
                 GE60186 
                 NM_001897.3 
                 CSPG4 
               
               
                   
                 GE54549 
                 NM_006574.2 
                 CSPG5 
               
               
                   
                 GE54158 
                 NM_005445.2 
                 CSPG6 
               
               
                   
                 GE60116 
                 NM_001904.2 
                 CTNNB1 
               
               
                   
                 GE63376 
                 NM_001511.1 
                 CXCL1 
               
               
                   
                 GE60012 
                 NM_004938.1 
                 DAPK1 
               
               
                   
                 GE54486 
                 NM_014326.2 
                 DAPK2 
               
               
                   
                 GE53147 
                 NM_001348.1 
                 DAPK3 
               
               
                   
                 GE79017 
                 NM_020548.4 
                 DBI 
               
               
                   
                 GE60014 
                 NM_005215.1 
                 DCC 
               
               
                   
                 GE55123 
                 NM_004942.2 
                 DEFB4 
               
               
                   
                 GE53874 
                 NM_015881.4 
                 DKK3 
               
               
                   
                 GE61043 
                 NM_004413.1 
                 DPEP1 
               
               
                   
                 GE54709 
                 NM_004147.3 
                 DRG1 
               
               
                   
                 GE60381 
                 NM_001943.1 
                 DSG2 
               
               
                   
                 GE56426 
                 NM_198057.1 
                 DSIPI 
               
               
                   
                 GE61271 
                 NM_004417.2 
                 DUSP1 
               
               
                   
                 GE59081 
                 NM_001948.2 
                 DUT 
               
               
                   
                 GE59467 
                 U80811.1 
                 EDG2 
               
               
                   
                 GE54109 
                 NM_004720.4 
                 EDG4 
               
               
                   
                 GE61188 
                 NM_012152.1 
                 EDG7 
               
               
                   
                 GE56653 
                 NM_004429.3 
                 EFNB1 
               
               
                   
                 GE58272 
                 NM_001963.2 
                 EGF 
               
               
                   
                 GE59632 
                 NM_005228.3 
                 EGFR 
               
               
                   
                 GE59464 
                 NM_015409.2 
                 EP400 
               
               
                   
                 GE80071 
                 NM_004441.3 
                 EPHB1 
               
               
                   
                 GE54191 
                 NM_004442.5 
                 EPHB2 
               
               
                   
                 GE62563 
                 NM_004444.4 
                 EPHB4 
               
               
                   
                 GE57332 
                 NM_004445.2 
                 EPHB6 
               
               
                   
                 GE54479 
                 NM_194356.1 
                 EPIM 
               
               
                   
                 GE57810 
                 NM_004448.2 
                 ERBB2 
               
               
                   
                 GE59651 
                 NM_000125.1 
                 ESR1 
               
               
                   
                 GE62899 
                 NM_016946.3 
                 F11R 
               
               
                   
                 GE81021 
                 NM_001443.1 
                 FABP1 
               
               
                   
                 GE79151 
                 NM_000134.2 
                 FABP2 
               
               
                   
                 GE80868 
                 NM_004102.2 
                 FABP3 
               
               
                   
                 GE79086 
                 NM_001444.1 
                 FABP5 
               
               
                   
                 GE55154 
                 NM_001446.3 
                 FABP7 
               
               
                   
                 GE60092 
                 NM_003824.2 
                 FADD 
               
               
                   
                 GE59061 
                 NM_004104.4 
                 FASN 
               
               
                   
                 GE62924 
                 NM_004111.4 
                 FEN1 
               
               
                   
                 GE54695 
                 NM_003862.1 
                 FGF18 
               
               
                   
                 GE79526 
                 NM_005130.3 
                 FGFBP1 
               
               
                   
                 GE59130 
                 NM_004496.2 
                 FOXA1 
               
               
                   
                 GE80477 
                 NM_021784.3 
                 FOXA2 
               
               
                   
                 GE81402 
                 NM_004497.2 
                 FOXA3 
               
               
                   
                 GE81766 
                 NM_012182.1 
                 FOXB1 
               
               
                   
                 GE80442 
                 NM_001453.1 
                 FOXC1 
               
               
                   
                 GE61182 
                 D63042.1 
                 FOXC2 
               
               
                   
                 GE59268 
                 NM_004472.1 
                 FOXD1 
               
               
                   
                 GE80316 
                 NM_004474.2 
                 FOXD2 
               
               
                   
                 GE614874 
                 NM_012183.1 
                 FOXD3 
               
               
                   
                 GE561268 
                 NM_207305.1 
                 FOXD4 
               
               
                   
                 GE59533 
                 NM_004473.3 
                 FOXE1 
               
               
                   
                 GE81767 
                 NM_012186.1 
                 FOXE3 
               
               
                   
                 GE61775 
                 NM_001451.1 
                 FOXF1 
               
               
                   
                 GE58940 
                 NM_001452.1 
                 FOXF2 
               
               
                   
                 GE59988 
                 NM_005249.3 
                 FOXG1B 
               
               
                   
                 GE79568 
                 NM_003923.1 
                 FOXH1 
               
               
                   
                 GE57620 
                 NM_012188.3 
                 FOXI1 
               
               
                   
                 GE817567 
                 AI684913.1 
                 FOXJ1 
               
               
                   
                 GE56857 
                 NM_018416.2 
                 FOXJ2 
               
               
                   
                 GE53710 
                 NM_014947.3 
                 FOXJ3 
               
               
                   
                 GE61025 
                 NM_181431.1 
                 FOXK2 
               
               
                   
                 GE481743 
                 NM_005250.1 
                 FOXL1 
               
               
                   
                 GE79861 
                 NM_023067.2 
                 FOXL2 
               
               
                   
                 GE59391 
                 NM_021953.2 
                 FOXM1 
               
               
                   
                 GE80086 
                 NM_003593.2 
                 FOXN1 
               
               
                   
                 GE573609 
                 NM_213596.1 
                 FOXN4 
               
               
                   
                 GE54250 
                 NM_002015.2 
                 FOXO1A 
               
               
                   
                 GE54251 
                 NM_001455.2 
                 FOXO3A 
               
               
                   
                 GE620465 
                 AI732568.1 
                 FOXP1 
               
               
                   
                 GE771702 
                 NM_148899.1 
                 FOXP2 
               
               
                   
                 GE503510 
                 NM_014009.2 
                 FOXP3 
               
               
                   
                 GE55167 
                 BM679319.1 
                 FOXP4 
               
               
                   
                 GE83634 
                 NM_033260.2 
                 FOXQ1 
               
               
                   
                 GE573639 
                 NM_181721.1 
                 FOXR1 
               
               
                   
                 GE525901 
                 NM_198451.1 
                 FOXR2 
               
               
                   
                 GE61934 
                 NM_002029.3 
                 FPR1 
               
               
                   
                 GE81028 
                 NM_001469.3 
                 G22P1 
               
               
                   
                 GE59654 
                 NM_000402.2 
                 G6PD 
               
               
                   
                 GE57684 
                 NM_001924.2 
                 GADD45A 
               
               
                   
                 GE82030 
                 NM_015675.1 
                 GADD45B 
               
               
                   
                 GE62138 
                 NM_006705.2 
                 GADD45G 
               
               
                   
                 GE81449 
                 NM_004864.1 
                 GDF15 
               
               
                   
                 GE80927 
                 NM_000581.2 
                 GPX1 
               
               
                   
                 GE81111 
                 NM_002083.2 
                 GPX2 
               
               
                   
                 GE695561 
                 AW129281.1 
                 GPX3 
               
               
                   
                 GE81112 
                 NM_002084.2 
                 GPX3 
               
               
                   
                 GE81113 
                 NM_002085.1 
                 GPX4 
               
               
                   
                 GE80647 
                 NM_003996.2 
                 GPX5 
               
               
                   
                 GE54767 
                 NM_015696.2 
                 GPX7 
               
               
                   
                 GE79962 
                 AF154054.1 
                 GREM1 
               
               
                   
                 GE88366 
                 CA437861.1 
                 GREM2 
               
               
                   
                 GE61362 
                 NM_000177.3 
                 GSN 
               
               
                   
                 GE54991 
                 NM_000637.2 
                 GSR 
               
               
                   
                 GE59100 
                 NM_000178.2 
                 GSS 
               
               
                   
                 GE79099 
                 NM_145740.2 
                 GSTA1 
               
               
                   
                 GE503167 
                 AI762244.1 
                 GSTA2 
               
               
                   
                 GE54166 
                 NM_000847.3 
                 GSTA3 
               
               
                   
                 GE61329 
                 NM_001512.2 
                 GSTA4 
               
               
                   
                 GE516052 
                 NM_153699.1 
                 GSTA5 
               
               
                   
                 GE61688 
                 NM_000561.2 
                 GSTM1 
               
               
                   
                 GE835116 
                 NM_000849.3 
                 GSTM3 
               
               
                   
                 GE57545 
                 NM_000851.2 
                 GSTM5 
               
               
                   
                 GE61334 
                 NM_000852.2 
                 GSTP1 
               
               
                   
                 GE60049 
                 NM_000853.1 
                 GSTT1 
               
               
                   
                 GE79395 
                 NM_033553.2 
                 GUCA2A 
               
               
                   
                 GE79398 
                 NM_007102.1 
                 GUCA2B 
               
               
                   
                 GE537019 
                 NM_005524.2 
                 HES1 
               
               
                   
                 GE62425 
                 NM_000601.3 
                 HGF 
               
               
                   
                 GE82322 
                 NM_018194.1 
                 HHAT 
               
               
                   
                 GE59057 
                 NM_001530.2 
                 HIF1A 
               
               
                   
                 GE60472 
                 NM_005338.4 
                 HIP1 
               
               
                   
                 GE568338 
                 NM_003493.2 
                 HIST3H3 
               
               
                   
                 GE659143 
                 NM_145904.1 
                 HMGA1 
               
               
                   
                 GE57571 
                 NM_000191.1 
                 HMGCL 
               
               
                   
                 GE59927 
                 NM_002130.4 
                 HMGCS1 
               
               
                   
                 GE60087 
                 NM_005518.2 
                 HMGCS2 
               
               
                   
                 GE61857 
                 NM_002133.1 
                 HMOX1 
               
               
                   
                 GE79731 
                 NM_005522.3 
                 HOXA1 
               
               
                   
                 GE88138 
                 NM_153715.1 
                 HOXA10 
               
               
                   
                 GE79995 
                 NM_005523.4 
                 HOXA11 
               
               
                   
                 GE80920 
                 NM_000522.2 
                 HOXA13 
               
               
                   
                 GE667398 
                 NM_006735.3 
                 HOXA2 
               
               
                   
                 GE83160 
                 NM_030661.3 
                 HOXA3 
               
               
                   
                 GE80064 
                 NM_002141.2 
                 HOXA4 
               
               
                   
                 GE57892 
                 NM_019102.2 
                 HOXA5 
               
               
                   
                 GE479776 
                 NM_024014.2 
                 HOXA6 
               
               
                   
                 GE483668 
                 NM_006896.2 
                 HOXA7 
               
               
                   
                 GE54105 
                 NM_002142.3 
                 HOXA9 
               
               
                   
                 GE59739 
                 NM_002144.2 
                 HOXB1 
               
               
                   
                 GE81628 
                 NM_006361.2 
                 HOXB13 
               
               
                   
                 GE59738 
                 NM_002145.2 
                 HOXB2 
               
               
                   
                 GE59740 
                 NM_002146.3 
                 HOXB3 
               
               
                   
                 GE56717 
                 NM_024015.3 
                 HOXB4 
               
               
                   
                 GE58143 
                 NM_002147.2 
                 HOXB5 
               
               
                   
                 GE82457 
                 NM_156036.1 
                 HOXB6 
               
               
                   
                 GE81403 
                 NM_004502.2 
                 HOXB7 
               
               
                   
                 GE79102 
                 NM_024016.2 
                 HOXB8 
               
               
                   
                 GE58746 
                 NM_017409.2 
                 HOXC10 
               
               
                   
                 GE497436 
                 NM_014212.2 
                 HOXC11 
               
               
                   
                 GE808308 
                 NM_173860.1 
                 HOXC12 
               
               
                   
                 GE80244 
                 NM_017410.2 
                 HOXC13 
               
               
                   
                 GE59694 
                 NM_014620.2 
                 HOXC4 
               
               
                   
                 GE59871 
                 NM_018953.2 
                 HOXC5 
               
               
                   
                 GE57846 
                 NM_153693.1 
                 HOXC6 
               
               
                   
                 GE812007 
                 NM_022658.3 
                 HOXC8 
               
               
                   
                 GE55497 
                 NM_006897.1 
                 HOXC9 
               
               
                   
                 GE82840 
                 NM_024501.1 
                 HOXD1 
               
               
                   
                 GE81125 
                 NM_002148.2 
                 HOXD10 
               
               
                   
                 GE82602 
                 NM_021192.2 
                 HOXD11 
               
               
                   
                 GE729613 
                 NM_021193.2 
                 HOXD12 
               
               
                   
                 GE80921 
                 NM_000523.2 
                 HOXD13 
               
               
                   
                 GE881059 
                 BQ941558.1 
                 HOXD4 
               
               
                   
                 GE59727 
                 NM_019558.2 
                 HOXD8 
               
               
                   
                 GE61129 
                 NM_014213.2 
                 HOXD9 
               
               
                   
                 GE57789 
                 NM_000860.3 
                 HPGD 
               
               
                   
                 GE57461 
                 NM_005343.2 
                 HRAS 
               
               
                   
                 GE53171 
                 BC041412.2 
                 HSPA12A 
               
               
                   
                 GE811123 
                 BX116887.1 
                 HSPA12B 
               
               
                   
                 GE82101 
                 NM_016299.1 
                 HSPA14 
               
               
                   
                 GE81493 
                 AK097113.1 
                 HSPA1A 
               
               
                   
                 GE81494 
                 NM_005346.3 
                 HSPA1B 
               
               
                   
                 GE62810 
                 NM_000201.1 
                 ICAM1 
               
               
                   
                 GE81127 
                 NM_002166.4 
                 ID2 
               
               
                   
                 GE59822 
                 NM_000618.2 
                 IGF1 
               
               
                   
                 GE80962 
                 NM_000875.2 
                 IGF1R 
               
               
                   
                 GE79183 
                 NM_000612.2 
                 IGF2 
               
               
                   
                 GE508441 
                 BC034757.1 
                 IHH 
               
               
                   
                 GE54386 
                 W52507.1 
                 IKBKAP 
               
               
                   
                 GE62527 
                 NM_001556.1 
                 IKBKB 
               
               
                   
                 GE61317 
                 NM_014002.2 
                 IKBKE 
               
               
                   
                 GE54691 
                 NM_003639.2 
                 IKBKG 
               
               
                   
                 GE61058 
                 NM_000572.2 
                 IL10 
               
               
                   
                 GE80144 
                 NM_000641.2 
                 IL11 
               
               
                   
                 GE563350 
                 NM_000575.3 
                 IL1A 
               
               
                   
                 GE79235 
                 NM_000576.2 
                 IL1B 
               
               
                   
                 GE902998 
                 NM_000586.2 
                 IL2 
               
               
                   
                 GE63369 
                 NM_020525.4 
                 IL22 
               
               
                   
                 GE53760 
                 NM_016584.2 
                 IL23A 
               
               
                   
                 GE59635 
                 NM_000417.1 
                 IL2RA 
               
               
                   
                 GE59660 
                 NM_000600.1 
                 IL6 
               
               
                   
                 GE61911 
                 NM_002211.2 
                 ITGB1 
               
               
                   
                 GE54170 
                 NM_181468.1 
                 ITGB4BP 
               
               
                   
                 GE59788 
                 NM_002231.2 
                 KAI1 
               
               
                   
                 GE61879 
                 NM_000238.2 
                 KCNH2 
               
               
                   
                 GE58431 
                 NM_007035.2 
                 KERA 
               
               
                   
                 GE53820 
                 BG912905.1 
                 KIAA1199 
               
               
                   
                 GE59676 
                 NM_000222.1 
                 KIT 
               
               
                   
                 GE86000 
                 NM_004235.3 
                 KLF4 
               
               
                   
                 GE61031 
                 NM_033360.2 
                 KRAS2 
               
               
                   
                 GE79418 
                 BU153499.1 
                 KRT8 
               
               
                   
                 GE60355 
                 NM_005562.1 
                 LAMC2 
               
               
                   
                 GE80131 
                 NM_002295.2 
                 LAMR1 
               
               
                   
                 GE80813 
                 NM_002300.3 
                 LDHB 
               
               
                   
                 GE56173 
                 NM_016269.2 
                 LEF1 
               
               
                   
                 GE60548 
                 NM_002306.1 
                 LGALS3 
               
               
                   
                 GE57621 
                 NM_005567.2 
                 LGALS3BP 
               
               
                   
                 GE61853 
                 NM_003667.2 
                 LGR5 
               
               
                   
                 GE60093 
                 NM_013975.1 
                 LIG3 
               
               
                   
                 GE61118 
                 NM_000627.2 
                 LTBP1 
               
               
                   
                 GE54721 
                 NM_006330.2 
                 LYPLA1 
               
               
                   
                 GE79416 
                 NM_000239.1 
                 LYZ 
               
               
                   
                 GE87934 
                 NM_032517.3 
                 LYZL1 
               
               
                   
                 GE573861 
                 NM_144634.2 
                 LYZL4 
               
               
                   
                 GE54752 
                 NM_020426.1 
                 LYZL6 
               
               
                   
                 GE534117 
                 NM_002745.2 
                 MAPK1 
               
               
                   
                 GE62730 
                 NM_002753.2 
                 MAPK10 
               
               
                   
                 GE88364 
                 NM_002751.5 
                 MAPK11 
               
               
                   
                 GE62595 
                 NM_002969.3 
                 MAPK12 
               
               
                   
                 GE54058 
                 NM_002754.3 
                 MAPK13 
               
               
                   
                 GE57735 
                 NM_001315.1 
                 MAPK14 
               
               
                   
                 GE79221 
                 NM_002746.1 
                 MAPK3 
               
               
                   
                 GE84984 
                 R87970.1 
                 MAPK4 
               
               
                   
                 GE79439 
                 NM_002748.2 
                 MAPK6 
               
               
                   
                 GE81188 
                 NM_139033.1 
                 MAPK7 
               
               
                   
                 GE57700 
                 NM_139046.1 
                 MAPK8 
               
               
                   
                 GE81189 
                 NM_002752.3 
                 MAPK9 
               
               
                   
                 GE59858 
                 NM_002382.3 
                 MAX 
               
               
                   
                 GE57107 
                 NM_004526.2 
                 MCM2 
               
               
                   
                 GE80542 
                 NM_130799.1 
                 MEN1 
               
               
                   
                 GE57468 
                 J02958.1 
                 MET 
               
               
                   
                 GE57913 
                 NM_002412.2 
                 MGMT 
               
               
                   
                 GE80049 
                 NM_145792.1 
                 MGST1 
               
               
                   
                 GE63001 
                 NM_032390.3 
                 MKI67IP 
               
               
                   
                 GE58891 
                 NM_000249.2 
                 MLH1 
               
               
                   
                 GE80495 
                 NM_002421.2 
                 MMP1 
               
               
                   
                 GE518683 
                 NM_002427.2 
                 MMP13 
               
               
                   
                 GE79854 
                 NM_002422.2 
                 MMP3 
               
               
                   
                 GE57525 
                 NM_004994.1 
                 MMP9 
               
               
                   
                 GE81153 
                 NM_002434.1 
                 MPG 
               
               
                   
                 GE58211 
                 NM_000251.1 
                 MSH2 
               
               
                   
                 GE59286 
                 NM_002439.1 
                 MSH3 
               
               
                   
                 GE60542 
                 NM_000179.1 
                 MSH6 
               
               
                   
                 GE53323 
                 NM_002442.2 
                 MSI1 
               
               
                   
                 GE88536 
                 N26272.1 
                 MSI2 
               
               
                   
                 GE57533 
                 NM_182741.1 
                 MUC1 
               
               
                   
                 GE81158 
                 NM_002457.1 
                 MUC2 
               
               
                   
                 GE86707 
                 AB038784.1 
                 MUC3B 
               
               
                   
                 GE82366 
                 NM_018406.2 
                 MUC4 
               
               
                   
                 GE60413 
                 AJ001402.1 
                 MUC5AC 
               
               
                   
                 GE564339 
                 U78550.1 
                 MUC5B 
               
               
                   
                 GE59609 
                 AK096772.1 
                 MUC6 
               
               
                   
                 GE57582 
                 NM_005962.3 
                 MXI1 
               
               
                   
                 GE57537 
                 NM_002467.2 
                 MYC 
               
               
                   
                 GE81665 
                 NM_006656.4 
                 NEU3 
               
               
                   
                 GE57992 
                 NM_003998.2 
                 NFKB1 
               
               
                   
                 GE81163 
                 NM_002502.2 
                 NFKB2 
               
               
                   
                 GE583888 
                 NM_145285.1 
                 NKX2-3 
               
               
                   
                 GE58970 
                 NM_000620.1 
                 NOS1 
               
               
                   
                 GE61880 
                 NM_000625.3 
                 NOS2A 
               
               
                   
                 GE57703 
                 NM_000603.3 
                 NOS3 
               
               
                   
                 GE58433 
                 NM_007052.3 
                 NOX1 
               
               
                   
                 GE57330 
                 NM_002519.1 
                 NPAT 
               
               
                   
                 GE79523 
                 NM_002524.2 
                 NRAS 
               
               
                   
                 GE59456 
                 NM_002528.4 
                 NTHL1 
               
               
                   
                 GE62798 
                 NM_004822.1 
                 NTN1 
               
               
                   
                 GE79384 
                 NM_006183.3 
                 NTS 
               
               
                   
                 GE79065 
                 NM_002538.2 
                 OCLN 
               
               
                   
                 GE59733 
                 NM_002539.1 
                 ODC1 
               
               
                   
                 GE58739 
                 NM_016819.2 
                 OGG1 
               
               
                   
                 GE80094 
                 NM_002583.2 
                 PAWR 
               
               
                   
                 GE61312 
                 NM_002592.2 
                 PCNA 
               
               
                   
                 GE61229 
                 NM_002634.2 
                 PHB 
               
               
                   
                 GE55121 
                 NM_004570.2 
                 PIK3C2G 
               
               
                   
                 GE85962 
                 NM_181523.1 
                 PIK3R1 
               
               
                   
                 GE57869 
                 NM_000300.2 
                 PLA2G2A 
               
               
                   
                 GE62645 
                 NM_005090.1 
                 PLA2G4B 
               
               
                   
                 GE54546 
                 NM_003706.1 
                 PLA2G4C 
               
               
                   
                 GE577920 
                 AB090876.1 
                 PLA2G4D 
               
               
                   
                 GE55263 
                 NM_004253.2 
                 PLAA 
               
               
                   
                 GE80967 
                 NM_000930.2 
                 PLAT 
               
               
                   
                 GE59641 
                 NM_002658.2 
                 PLAU 
               
               
                   
                 GE80529 
                 NM_002659.2 
                 PLAUR 
               
               
                   
                 GE58900 
                 NM_006225.1 
                 PLCD1 
               
               
                   
                 GE86096 
                 NM_133373.2 
                 PLCD3 
               
               
                   
                 GE83496 
                 NM_032726.2 
                 PLCD4 
               
               
                   
                 GE81175 
                 NM_002660.2 
                 PLCG1 
               
               
                   
                 GE57955 
                 NM_002661.1 
                 PLCG2 
               
               
                   
                 GE54324 
                 NM_002663.2 
                 PLD2 
               
               
                   
                 GE58954 
                 NM_000535.2 
                 PMS2 
               
               
                   
                 GE61315 
                 CD356988.1 
                 POLB 
               
               
                   
                 GE60200 
                 NM_002693.1 
                 POLG 
               
               
                   
                 GE54124 
                 NM_003711.2 
                 PPAP2A 
               
               
                   
                 GE86713 
                 NM_177414.1 
                 PPAP2B 
               
               
                   
                 GE54290 
                 NM_003712.2 
                 PPAP2C 
               
               
                   
                 GE56066 
                 NM_006238.2 
                 PPARD 
               
               
                   
                 GE54254 
                 NM_005037.3 
                 PPARG 
               
               
                   
                 GE62667 
                 NM_013261.2 
                 PPARGC1A 
               
               
                   
                 GE59698 
                 NM_002730.3 
                 PRKACA 
               
               
                   
                 GE652786 
                 AW467479.1 
                 PRKACB 
               
               
                   
                 GE577011 
                 NM_002732.2 
                 PRKACG 
               
               
                   
                 GE61216 
                 M33336.1 
                 PRKAR1A 
               
               
                   
                 GE58041 
                 NM_002735.1 
                 PRKAR1B 
               
               
                   
                 GE57918 
                 NM_002736.2 
                 PRKAR2B 
               
               
                   
                 GE86264 
                 NM_002737.2 
                 PRKCA 
               
               
                   
                 GE59687 
                 NM_002738.5 
                 PRKCB1 
               
               
                   
                 GE57042 
                 NM_006254.3 
                 PRKCD 
               
               
                   
                 GE611116 
                 AK025126.1 
                 PRKCE 
               
               
                   
                 GE57971 
                 NM_006255.3 
                 PRKCH 
               
               
                   
                 GE57727 
                 L33881.1 
                 PRKCI 
               
               
                   
                 GE79759 
                 NM_006257.2 
                 PRKCQ 
               
               
                   
                 GE62614 
                 NM_006904.6 
                 PRKDC 
               
               
                   
                 GE54213 
                 NM_006017.1 
                 PROM1 
               
               
                   
                 GE57041 
                 NM_000952.3 
                 PTAFR 
               
               
                   
                 GE59570 
                 NM_000314.2 
                 PTEN 
               
               
                   
                 GE79421 
                 NM_000955.2 
                 PTGER1 
               
               
                   
                 GE58989 
                 NM_000956.2 
                 PTGER2 
               
               
                   
                 GE80971 
                 NM_198714.1 
                 PTGER3 
               
               
                   
                 GE57688 
                 NM_000958.2 
                 PTGER4 
               
               
                   
                 GE55312 
                 NM_004878.3 
                 PTGES 
               
               
                   
                 GE87476 
                 NM_198938.1 
                 PTGES2 
               
               
                   
                 GE54054 
                 NM_000959.2 
                 PTGFR 
               
               
                   
                 GE53970 
                 NM_020440.2 
                 PTGFRN 
               
               
                   
                 GE57997 
                 M59979.1 
                 PTGS1 
               
               
                   
                 GE62312 
                 NM_000963.1 
                 PTGS2 
               
               
                   
                 GE79453 
                 NM_005607.3 
                 PTK2 
               
               
                   
                 GE59167 
                 NM_173174.1 
                 PTK2B 
               
               
                   
                 GE57124 
                 NM_006908.3 
                 RAC1 
               
               
                   
                 GE56475 
                 NM_002878.2 
                 RAD51L3 
               
               
                   
                 GE58929 
                 NM_002879.2 
                 RAD52 
               
               
                   
                 GE57879 
                 NM_002890.1 
                 RASA1 
               
               
                   
                 GE81207 
                 NM_002895.2 
                 RBL1 
               
               
                   
                 GE60009 
                 NM_005611.2 
                 RBL2 
               
               
                   
                 GE58291 
                 NM_002899.2 
                 RBP1 
               
               
                   
                 GE57895 
                 NM_002909.3 
                 REG1A 
               
               
                   
                 GE61112 
                 NM_002908.2 
                 REL 
               
               
                   
                 GE61225 
                 BC033522.1 
                 RELA 
               
               
                   
                 GE58104 
                 NM_006509.2 
                 RELB 
               
               
                   
                 GE61154 
                 X52773.1 
                 RXRA 
               
               
                   
                 GE59677 
                 NM_002964.3 
                 S100A8 
               
               
                   
                 GE80079 
                 NM_002965.2 
                 S100A9 
               
               
                   
                 GE87242 
                 NM_133491.2 
                 SAT2 
               
               
                   
                 GE53772 
                 NM_005063.4 
                 SCD 
               
               
                   
                 GE82995 
                 NM_024906.1 
                 SCD4 
               
               
                   
                 GE58925 
                 NM_002979.3 
                 SCP2 
               
               
                   
                 GE60412 
                 NM_002997.4 
                 SDC1 
               
               
                   
                 GE57514 
                 NM_002998.3 
                 SDC2 
               
               
                   
                 GE56057 
                 NM_000450.1 
                 SELE 
               
               
                   
                 GE57883 
                 NM_000655.2 
                 SELL 
               
               
                   
                 GE58293 
                 NM_003005.2 
                 SELP 
               
               
                   
                 GE62796 
                 NM_000295.3 
                 SERPINA1 
               
               
                   
                 GE58697 
                 NM_016186.1 
                 SERPINA10 
               
               
                   
                 GE88319 
                 BX248259.1 
                 SERPINA11 
               
               
                   
                 GE87109 
                 NM_173850.2 
                 SERPINA12 
               
               
                   
                 GE60232 
                 NM_002575.1 
                 SERPINB2 
               
               
                   
                 GE57824 
                 NM_000602.1 
                 SERPINE1 
               
               
                   
                 GE79528 
                 NM_006142.3 
                 SFN 
               
               
                   
                 GE54530 
                 NM_003012.3 
                 SFRP1 
               
               
                   
                 GE527352 
                 NM_003013.2 
                 SFRP2 
               
               
                   
                 GE62558 
                 NM_003015.2 
                 SFRP5 
               
               
                   
                 GE619667 
                 NM_000193.2 
                 SHH 
               
               
                   
                 GE62087 
                 NM_021805.1 
                 SIGIRR 
               
               
                   
                 GE81228 
                 NM_003051.2 
                 SLC16A1 
               
               
                   
                 GE57541 
                 NM_006516.1 
                 SLC2A1 
               
               
                   
                 GE56147 
                 AI792874.1 
                 SLC5A12 
               
               
                   
                 GE558682 
                 NM_145913.2 
                 SLC5A8 
               
               
                   
                 GE54526 
                 NM_004787.1 
                 SLIT2 
               
               
                   
                 GE60408 
                 NM_003071.2 
                 SMARCA3 
               
               
                   
                 GE54831 
                 NM_005631.3 
                 SMO 
               
               
                   
                 GE59855 
                 NM_000543.3 
                 SMPD1 
               
               
                   
                 GE58315 
                 NM_003877.3 
                 SOCS2 
               
               
                   
                 GE79683 
                 NM_000454.4 
                 SOD1 
               
               
                   
                 GE80932 
                 NM_000636.1 
                 SOD2 
               
               
                   
                 GE545368 
                 NM_003118.2 
                 SPARC 
               
               
                   
                 GE61335 
                 NM_000582.2 
                 SPP1 
               
               
                   
                 GE61402 
                 NM_003150.3 
                 STAT3 
               
               
                   
                 GE83532 
                 NM_032811.1 
                 TBRG1 
               
               
                   
                 GE57183 
                 NM_201636.1 
                 TBXA2R 
               
               
                   
                 GE58073 
                 NM_003199.1 
                 TCF4 
               
               
                   
                 GE80031 
                 NM_003219.1 
                 TERT 
               
               
                   
                 GE81248 
                 NM_003220.1 
                 TFAP2A 
               
               
                   
                 GE57647 
                 NM_003226.2 
                 TFF3 
               
               
                   
                 GE59644 
                 NM_000660.2 
                 TGFB1 
               
               
                   
                 GE55238 
                 NM_006022.2 
                 TGFB1I4 
               
               
                   
                 GE81250 
                 NM_003238.1 
                 TGFB2 
               
               
                   
                 GE59720 
                 NM_003239.1 
                 TGFB3 
               
               
                   
                 GE61621 
                 NM_000358.1 
                 TGFBI 
               
               
                   
                 GE578892 
                 NM_003242.3 
                 TGFBR2 
               
               
                   
                 GE80065 
                 NM_003241.1 
                 TGM4 
               
               
                   
                 GE78973 
                 S78453.1 
                 TIMP3 
               
               
                   
                 GE81254 
                 NM_003257.2 
                 TJP1 
               
               
                   
                 GE54434 
                 NM_003264.2 
                 TLR2 
               
               
                   
                 GE59576 
                 NM_003266.2 
                 TLR4 
               
               
                   
                 GE54433 
                 NM_003268.3 
                 TLR5 
               
               
                   
                 GE56816 
                 NM_016192.2 
                 TMEFF2 
               
               
                   
                 GE59636 
                 NM_000594.2 
                 TNF 
               
               
                   
                 GE79493 
                 NM_021137.3 
                 TNFAIP1 
               
               
                   
                 GE62903 
                 NM_003844.2 
                 TNFRSF10A 
               
               
                   
                 GE54131 
                 NM_003842.3 
                 TNFRSF10B 
               
               
                   
                 GE54132 
                 NM_003841.2 
                 TNFRSF10C 
               
               
                   
                 GE54225 
                 AF029761.1 
                 TNFRSF10D 
               
               
                   
                 GE562184 
                 NM_003839.2 
                 TNFRSF11A 
               
               
                   
                 GE59899 
                 NM_000043.3 
                 TNFRSF6 
               
               
                   
                 GE62504 
                 NM_032945.2 
                 TNFRSF6B 
               
               
                   
                 GE59115 
                 NM_003810.2 
                 TNFSF10 
               
               
                   
                 GE79109 
                 NM_003701.2 
                 TNFSF11 
               
               
                   
                 GE784965 
                 NM_000639.1 
                 TNFSF6 
               
               
                   
                 GE55270 
                 D62608.1 
                 TOLLIP 
               
               
                   
                 GE58227 
                 NM_000546.2 
                 TP53 
               
               
                   
                 GE60333 
                 NM_003722.3 
                 TP73L 
               
               
                   
                 GE79329 
                 NM_003295.1 
                 TPT1 
               
               
                   
                 GE61891 
                 NM_003313.2 
                 TSTA3 
               
               
                   
                 GE59639 
                 NM_001071.1 
                 TYMS 
               
               
                   
                 GE840631 
                 BF516171.1 
                 TYMS 
               
               
                   
                 GE495741 
                 NM_021833.3 
                 UCP1 
               
               
                   
                 GE59585 
                 NM_003355.2 
                 UCP2 
               
               
                   
                 GE59501 
                 NM_022803.1 
                 UCP3 
               
               
                   
                 GE57479 
                 NM_000376.1 
                 VDR 
               
               
                   
                 GE59158 
                 NM_005429.2 
                 VEGFC 
               
               
                   
                 GE59707 
                 NM_007127.1 
                 VIL1 
               
               
                   
                 GE63384 
                 NM_005430.2 
                 WNT1 
               
               
                   
                 GE83129 
                 NM_025216.2 
                 WNT10A 
               
               
                   
                 GE59476 
                 NM_003394.2 
                 WNT10B 
               
               
                   
                 GE81421 
                 NM_004626.2 
                 WNT11 
               
               
                   
                 GE59699 
                 NM_003391.1 
                 WNT2 
               
               
                   
                 GE63181 
                 NM_024494.1 
                 WNT2B 
               
               
                   
                 GE86328 
                 NM_030753.3 
                 WNT3 
               
               
                   
                 GE507271 
                 NM_033131.2 
                 WNT3A 
               
               
                   
                 GE62675 
                 NM_030761.3 
                 WNT4 
               
               
                   
                 GE57670 
                 BQ942339.1 
                 WNT5A 
               
               
                   
                 GE61657 
                 NM_032642.2 
                 WNT5B 
               
               
                   
                 GE63133 
                 W79066.1 
                 WNT6 
               
               
                   
                 GE62528 
                 NM_004625.3 
                 WNT7A 
               
               
                   
                 GE507187 
                 NM_058238.1 
                 WNT7B 
               
               
                   
                 GE897460 
                 NM_058244.1 
                 WNT8A 
               
               
                   
                 GE80654 
                 NM_003393.2 
                 WNT8B 
               
               
                   
                 GE80087 
                 NM_003395.1 
                 WNT9A 
               
               
                   
                 GE543960 
                 NM_003396.1 
                 WNT9B 
               
               
                   
                 GE62786 
                 NM_000380.2 
                 XPA 
               
               
                   
                 GE81853 
                 NM_003404.3 
                 YWHAB 
               
               
                   
                 GE59242 
                 NM_006761.3 
                 YWHAE 
               
               
                   
                 GE53664 
                 NM_012479.2 
                 YWHAG 
               
               
                   
                 GE60439 
                 NM_003405.2 
                 YWHAH 
               
               
                   
                 GE80214 
                 NM_006826.2 
                 YWHAQ 
               
               
                   
                 GE844420 
                 BF508115.1 
                 YWHAZ 
               
               
                   
                 GE81678 
                 BQ945983.1 
                 ZBTB33 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE VI 
               
               
                   
               
               
                 A j   k  ∩B 
                 k = 1.5 
                 k = 2 
                 k = 2.5 
                 k = 3 
               
               
                   
               
             
            
               
                 j = 0 
                 50 
                 36 
                 23 
                 10 
               
               
                 j = 1 
                 65 
                 54 
                 35 
                 18 
               
               
                 j = 2 
                 84 
                 61 
                 46 
                 29 
               
               
                 j = 3 
                 94 
                 70 
                 51 
                 37 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
             
               
                 TABLE VII 
               
               
                   
               
               
                   
                   
                 Common Genes 
               
               
                 Classification Groups 
                 Sample Size 
                 in A 1   2  ∩ B 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 (+IR, +Polyps) VS (−IR, −Polyps) at BL1 
                 12 
                 97 
               
               
                 (+IR, +Polyps) on Control VS (+IR, +Polyps) on Legume 
                 11 
                 103 
               
               
                 (−IR, −Polyps) on Control VS (−IR, −Polyps) on Legume 
                 12 
                 145 
               
               
                 (+IR, +Polyps) on Control VS (−IR, −Polyps) on Control 
                 11 
                 121 
               
               
                 (+IR, +Polyps) on Legume VS (−IR, −Polyps) on Legume 
                 12 
                 114 
               
               
                 (+IR, +Polyps) VS (−IR, −Polyps) at BL1 &amp; BL2 
                 21 
                 92 
               
               
                 (+Polyps) VS (−Polyps) at BL1 
                 23 
                 64 
               
               
                 (+IR) VS (−IR) at BL1 
                 23 
                 64 
               
               
                 (+Polyps) VS (−Polyps) at BL1 &amp; BL2 
                 41 
                 59 
               
               
                 (+Polyps) on Control VS (+Polyps) on Legume 
                 21 
                 87 
               
               
                 (+IR) on Control VS (+IR) on Legume 
                 23 
                 74 
               
               
                 (+IR) VS (−IR) at all time points 
                 86 
                 54 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE VIII 
               
               
                   
                   
               
               
                   
                 Gene name 
                 p-value 
                 Fold change 
               
               
                   
                   
               
             
            
               
                   
                 ALOX12B 
                 0.1841 
                 0.6486 
               
               
                   
                 BECN1 
                 0.0580 
                 0.5140 
               
               
                   
                 CDK4 
                 0.0370 
                 0.5787 
               
               
                   
                 DAPK1 
                 0.0639 
                 1.1258 
               
               
                   
                 HOXA3 
                 0.0202 
                 1.0712 
               
               
                   
                 HOXC6 
                 0.0134 
                 0.4352 
               
               
                   
                 ID2 
                 0.0626 
                 0.9413 
               
               
                   
                 IGF1R 
                 0.0040 
                 0.4537 
               
               
                   
                 MAPK11 
                 0.6291 
                 0.7521 
               
               
                   
                 NOS3 
                 0.0285 
                 0.4451 
               
               
                   
                 TJP1 
                 0.0168 
                 0.6092 
               
               
                   
                 uCP2 
                 0.6330 
                 0.7669 
               
               
                   
                 WNT1 
                 0.7147 
                 0.8290 
               
               
                   
                 YWHAZ 
                 0.0298 
                 0.4901