Datasets:

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Variome_split_0404_dev

like 0

[ "Hereditary", "nonpolyposis", "colorectal", "cancer", "(HNPCC)", "is", "an", "autosomal", "dominant", "syndrome.", "The", "National", "Cancer", "Institute", "(NCI)", "has", "recommended", "the", "Revised", "Bethesda", "guidelines", "for", "screening", "HNPCC.", "There", "has", "been", "a", "great", "deal", "of", "research", "on", "the", "value", "of", "these", "tests", "in", "other", "countries.", "However,", "literature", "about", "the", "Chinese", "population", "is", "scarce.", "Our", "objective", "is", "to", "detect", "and", "study", "microsatellite", "instability", "(MSI)", "and", "mismatch", "repair", "(MMR)", "gene", "germline", "mutation", "carriers", "among", "a", "Chinese", "population", "with", "colorectal", "cancer." ]

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[ "In", "order", "to", "determine", "whether", "the", "characteristic", "clinicopathological", "features", "of", "tumors", "with", "BRAF", "mutation", "were", "due", "to", "their", "close", "association", "with", "MSI+", "and", "CIMP+,", "we", "stratified", "tumours", "according", "to", "these", "phenotypes.", "Despite", "having", "only", "9", "MSI-/BRAF", "mutant", "and", "5", "CIMP-/BRAF", "mutant", "tumors,", "the", "results", "showed", "that", "associations", "between", "BRAF", "mutation", "and", "the", "morphological", "properties", "of", "tumor-infiltrating", "infiltrating", "lymphocytes,", "poor", "histological", "grade", "and", "mucinous", "phenotype", "were", "retained", "(Tables", "3", "and", "4)." ]

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[ "Note:", "no", "result", "for", "KRAS", "in", "one", "sessile", "serrated", "adenoma", "(SSA)", "and", "one", "adenomas", " ", "that", "had", "any", "BRAF", "mutations", "at", "all.", "Mutation", "frequencies", "for", "both", "KRAS", "and", "BRAF", "were", "distributed", "differently", "across", "the", "seven", "polyp", "groups", "(Table", "1)." ]

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[ "Multiple", "differences", "between", "these", "studies", "could", "have", "caused", "the", "wide", "range", "in", "the", "MSI", "frequency", "(0–39%).", "One", "of", "these", "is", "the", "number", "and", "variety", "of", "microsatellite", "markers", "analyzed", "to", "determine", "the", "MSI.", "The", "NCI", "recommended", "five", "markers", "comprising", "the", "National", "Cancer", "Institute", "Consensus", "Panel", "(NCI-CP)", "for", "the", "detection", "of", "MSI,", "i.e.", "markers", "for", "the", "mononucleotide", "repeats", "BAT25", "and", "BAT26", "and", "the", "dinucleotide", "repeats", "D2S123,", "D5S346", "and", "D17S250", "[48].", "Table", "2", "shows", "per", "study", "the", "number", "of", "MS", "markers", "used", "and", "specifies", "how", "many", "of", "these", "are", "part", "of", "the", "NCI-CP.", "Interestingly,", "the", "studies", "that", "used", "all", "NCI-CP", "markers", "to", "determine", "the", "MS", "status", "also", "showed", "a", "wide", "range", "in", "MSI", "frequency", "(8–39%)", "which", "is", "similar", "to", "the", "overall", "range", "(0–39%).", "Therefore,", "the", "various", "MS", "markers", "used", "cannot", "be", "the", "sole", "cause", "for", "the", "wide", "range.", "Moreover,", "Gras", "et", "al.", "suggest", "that", "the", "reliability", "of", "the", "mononucleotide", "markers", "BAT25", "and", "BAT26", "is", "so", "high", "that", "most", "MSI", "can", "be", "predicted", "by", "evaluating", "these", "two", "markers", "exclusively", "[27],", "confirming", "the", "less", "stringent", "role", "for", "the", "various", "markers", "used", "for", "the", "analysis." ]

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[ "This", "paper", "explores", "the", "possibility", "that", "the", "early", "evolution", "of", "colorectal", "cancer", " ", "is", "not", "limited", "to", "two", "essentially", "independent", "pathways,", "but", "often", "combines", "components", "of", "these", "pathways.", "Indeed,", "the", "successful", "‘fusion’", "of", "the", "hyperproliferation", "and", "crypt", "fission", "that", "characterize", "adenomas21", "with", "the", "inhibition", "of", "apoptosis", "that", "has", "been", "linked", "with", "serrated", "polyps22,23", "may", "generate", "lesions", "with", "enhanced", "aggressiveness", "MP", ")", "or", "could", "develop", "as", "de", "novo", "SA", "but", "through", "mechanisms", "shared", "with", "HPs.", "This", "proposal", "subsequently", "received", "strong", "support", "through", "the", "demonstration", "of", "molecular", "alterations", "common", "to", "both", "types", "of", "serrated", "polyp", ",", "notably", "mutation", "of", "BRAF", "and", "extensive", "DNA", "methylation.12", "This", "viewpoint", "was", "consolidated", "through", "the", "formal", "recognition", "of", "two", "largely", "independent", "pathways", "of", "colorectal", "tumorigenesis:", "(i)", "the", "traditional", "adenoma–carcinoma", "sequence", "associated", "with", "chomosomally", "unstable", "CRCs,13", "and", "(ii)", "the", "‘serrated", "pathway’", "culminating", "in", "CRCs", "chomosomally", "unstable", " ", "CRCs,13", "and", "(ii)", "the", "‘serrated", "pathway’", "culminating", "in", "CRCs", "with", "DNA", "microsatellite", "instability", "(MSI),", "mutation", "of", "BRAF", "and", "extensive", "DNA", "methylation.12,14–20" ]

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[ "Evaluation", "of", "data", "set", "quality", "by", "tissue-wise", "hierarchical", "clustering" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "For", "the", "SEER", "dataset,", "we", "also", "fit", "our", "model", "for", "cancer", "progression", "[11]", "with", "the", "inferential", "method", "described", "in", "reference", "12.", "This", "method", "does", "not", "require", "a", "life", "table,", "but", "unlike", "our", "method", "it", "does", "require", "information", "on", "all", "the", "cancer", "cancer", "cancers", "white", "rectum", "cancer", "MLH1", " ", "or", "MSH2", " ", "were", "detected", "by", "allelic", "specific", "PCR", "assays", "(for", "the", "two", "common", "Finnish", "MLH1", "cancers", "colorectal", " ", "cancers", "sampled", "from", "nine", "large", "regional", "hospitals", "in", "southeastern", "Finland", " ", "as", "part", "of", "a", "study", "to", "characterize", "genetic", "alterations", "in", "a", "well-defined", "population", "[9].", "The", "cancers", "represent", "approximately", "60%", "of", "all", "colorectal", " ", "cancers", "removed", "from", "this", "population", "in", "1994", "to", "1998", "[9].", "Germline", "mutations", "in", "MLH1", "or", "MSH2", "were", "detected", "by", "allelic", "specific", "PCR", "assays", "(for", "the", "two", "common", "Finnish", "MLH1", "germline", "mutations)", "or", "by", "direct", "genomic", "sequencing", "of", "coding", "exons", "[9].", "The", "data", "can", "be", "downloaded", "from", "the", "following", "website:", ".", "Approval", "for", "this", "research", "was", "obtained", "from", "the", "appropriate", "ethics", "committees,", "which", "are", "in", "compliance", "with", "the", "Helsinki", "Declaration." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 25, 3, 1, 21, 0, 0, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 9, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 25, 26, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "The", "accelerated", "development", "of", "genetic", "counselling", "in", "cancer", "during", "the", "past", "few", "years", "is", "due", "to", "the", "feedback", "and", "interactive", "information", "sharing", "on", "genetic", "studies,", "clinical", "management", "and", "psychological", "issues", "in", "families", "with", "a", "high", "risk", "of", "cancer.", "Identification", "of", "deleterious", "variants", "in", "such", "families", "is", "essential", "for", "accurate", "assessment", "of", "individual", "risk", "and,", "if", "required,", "subsequent", "inclusion", "into", "a", "personalized", "surveillance", "programme." ]

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[ "MLH1", "promoter", "hypermethylation", "by", "Methylation", "Sensitive", "Multiplex", "Ligation-dependent", "Probe", "Amplification", "(MS-MLPA),", "and", "BRAF", "p.Val600Glu", "mutation", "by", "direct", "sequencing", "from", "tumor", "DNA", "was", "also", "assess", "when", "MLH1", "loss", "of", "expression", "was", "detected." ]

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[ "At", "present,", "a", "number", "of", "publications", "have", "studied", "the", "value", "of", "the", "revised", "Bethesda", "criteria", "and", "the", "relevant", "diagnostic", "procedures", "[13,14].", "However,", "there", "has", "not", "been", "any", "systematic", "report", "on", "germline", "mutations", "of", "MMR", "genes", "in", "the", "Chinese", "population.", "Moreover,", "we", "found", "that", "research", "from", "some", "countries", "have", "results", "that,", "if", "applied", "to", "the", "NCI", "recommendations,", "may", "have", "resulted", "in", "a", "missed", "HNPCC", "family", "or", "low", "pick-up", "rate", "of", "HNPCC.", "In", "a", "study", "by", "Pinol", "et", "al.", "from", "Spain", "[13],", "287", "out", "of", "1222", "patients", "(23.5%)", "complied", "with", "the", "revised", "Bethesda", "standard.", "Ninety-one", "patients", "(7.4%)", "were", "MSI", "carriers,", "but", "only", "11", "patients", "(0.9%)", "had", "germline", "mutations", "of", "MSH2", "or", "MLH1.", "This", "means", "that", "among", "this", "group,", "only", "0.9%", "of", "patients", "could", "be", "diagnosed", "as", "HNPCC.", "In", "a", "study", "by", "Yearsley", "et", "al.", "[14],", "out", "of", "482", "US", "patients", "with", "colorectal", "cancers,", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers,", "the", "MLH1", "hypermethylation", "occurred", "in", "89%", "of", "patients.", "Bettstetter", "et", "al.", "[20]", "showed", "that", "all", "sporadic", "MSI-H", "CRCs", "were", "hypermethylated", "at", "the", "MLH1", "promoter.", "These", "results", "were", "similar", "to", "ours.", "Fourteen", "out", "of", "16", "MLH1", "negatively", "staining", "CRCs", "were", "hypermethylated", "at", "the", "MLH1promoter.", "Mutation", "analysis", "revealed", "that", "8", "patients", "(23.5%)", "had", "MMR", "gene", "germline", "mutations", "out", "of", "34", "MSI", "patients.", "Five", "patients", "had", "MSH2", "mutations", "and", "3", "had", "MSH6", "mutations,", "while", "no", "population", ".", "Moreover,", "we", "found", "that", "research", "from", "some", "countries", "have", "results", "that,", "if", "applied", "to", "the", "NCI", "recommendations,", "may", "have", "resulted", "in", "a", "missed", "HNPCC", "family", "or", "low", "pick-up", "rate", "of", "HNPCC.", "In", "a", "study", "by", "Pinol", "et", "al.", "from", "Spain", " ", "[13],", "287", "out", "of", "1222", "patients", "(23.5%)", "complied", "with", "the", "revised", "Bethesda", "standard.", "Ninety-one", "patients", "(7.4%)", "were", "MSI", "carriers,", "but", "only", "11", "patients", "(0.9%)", "had", "germline", "mutations", "of", "MSH2", "or", "MLH1.", "This", "means", "that", "among", "this", "group,", "only", "0.9%", "of", "patients", "could", "be", "diagnosed", "as", "HNPCC.", "In", "a", "study", "by", "Yearsley", "et", "al.", "[14],", "out", "of", "482", "US", "patients", "with", "colorectal", "cancers,", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer", "MSI", "carriers", ",", "but", "only", "11", "patients", "(0.9%)", "had", "germline", "mutations", " ", "of", "MSH2", "or", "MLH1.", "This", "means", "that", "among", "this", "group,", "only", "0.9%", "of", "patients", "could", "be", "diagnosed", "as", "HNPCC.", "In", "a", "study", "by", "Yearsley", "et", "al.", "[14],", "out", "of", "482", "US", "patients", "with", "colorectal", "cancers,", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", " ", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", " ", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers,", "the", "MLH1", "hypermethylation", "occurred", "in", "89%", "of", "patients.", "Bettstetter", "et", "al.", "[20]", "showed", "that", "all", "sporadic", "MSI-H", "CRCs", "were", "hypermethylated", "at", "the", "MLH1", "promoter.", "These", "results", "were", "similar", "to", "ours.", "Fourteen", "out", "of", "16", "MLH1", "negatively", "staining", "CRCs", "were", "hypermethylated", "at", "the", "MLH1promoter.", "Mutation", "analysis", "revealed", "that", "8", "patients", "(23.5%)", "had", "MMR", "gene", "germline", "mutations", "out", "of", "34", "MSI", "patients.", "Five", "patients", "had", "MSH2", "mutations", "and", "3", "had", "MSH6", "mutations,", "while", "no", "MLH1", "mutation", "was", "found.", "There", "were", "2", "and", "6", "patients", "who", "had", "mutations", "in", "MSH2", "and", "MSH6", "in", "the", "MSI-L", "and", "MSI-H", "groups,", "respectively.", "Yearsley", "et", "al.", "[15],", "in", "their", "study", "of", "87", "patients", "with", "MSI", "colorectal", "cancers,", "found", "12", "patients", "(13.8%)", "with", "MLH1", "and", "MSH2", "germline", "mutations.", "Niessen", "et", "al.", "[16],", "however,", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "was", "82%", "33.3%", "colorectal", "cancers", "US", " ", "patients", "with", "colorectal", " ", "cancers,", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", " ", "CRCs", ".", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", " ", "MSI", " ", "CRCs", " ", "had", "MLH1", "promoter", "hypermethylation", ",", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers,", "the", "MLH1", "hypermethylation", "occurred", "in", "89%", "of", "patients.", "Bettstetter", "et", "al.", "[20]", "showed", "that", "all", "sporadic", "MSI-H", "CRCs", "were", "hypermethylated", "at", "the", "MLH1", "promoter.", "These", "results", "were", "similar", "to", "ours.", "Fourteen", "out", "of", "16", "MLH1", "negatively", "staining", "CRCs", "were", "hypermethylated", "at", "the", "MLH1promoter.", "Mutation", "analysis", "revealed", "that", "8", "patients", "(23.5%)", "had", "MMR", "gene", "germline", "mutations", "out", "of", "34", "MSI", "patients.", "Five", "patients", "had", "MSH2", "mutations", "and", "3", "had", "MSH6", "mutations,", "while", "no", "MLH1", "mutation", "was", "found.", "There", "were", "2", "and", "6", "patients", "who", "had", "mutations", "in", "MSH2", "and", "MSH6", "in", "the", "MSI-L", "and", "MSI-H", "groups,", "respectively.", "Yearsley", "et", "al.", "[15],", "in", "their", "study", "of", "87", "patients", "with", "MSI", "colorectal", "cancers,", "found", "12", "patients", "(13.8%)", "with", "MLH1", "and", "MSH2", "germline", "mutations.", "Niessen", "et", "al.", "[16],", "however,", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "was", "82%", "in", "the", "young", "age", "group", "(<50", "years", "old).", "This", "was", "quite", "different", "from", "our", "group.", "This", "difference", "might", "be", "due", "to", "different", "case", "87", " ", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "2.5%", ")", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "cancers", ",", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers,", "the", "MLH1", "hypermethylation", "occurred", "in", "89%", "of", "patients.", "Bettstetter", "et", "al.", "[20]", "showed", "that", "all", "sporadic", "MSI-H", "CRCs", "were", "hypermethylated", "at", "the", "MLH1", "promoter.", "These", "results", "were", "similar", "to", "ours.", "Fourteen", "out", "of", "16", "MLH1", "negatively", "staining", "CRCs", "were", "hypermethylated", "at", "the", "MLH1promoter.", "Mutation", "analysis", "revealed", "that", "8", "patients", "(23.5%)", "had", "MMR", "gene", "germline", "mutations", "out", "of", "34", "MSI", "patients.", "Five", "patients", "had", "MSH2", "mutations", "and", "3", "had", "MSH6", "mutations,", "while", "no", "MLH1", "mutation", "was", "found.", "There", "were", "2", "and", "6", "patients", "who", "had", "mutations", "in", "MSH2", "and", "MSH6", "in", "the", "MSI-L", "and", "MSI-H", "groups,", "respectively.", "Yearsley", "et", "al.", "[15],", "in", "their", "study", "of", "87", "patients", "with", "MSI", "colorectal", "cancers,", "found", "12", "patients", "(13.8%)", "with", "MLH1", "and", "MSH2", "germline", "mutations.", "Niessen", "et", "al.", "[16],", "however,", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "was", "82%", "in", "the", "young", "age", "group", "(<50", "years", "old).", "This", "was", "quite", "different", "from", "our", "group.", "This", "difference", "might", "be", "due", "to", "different", "case", "selections", "of", "the", "two", "groups.", "Our", "study", "was", "more", "representative", "of", "the", "patient", "population", "because", "it", "was", "a", "successive", "cohort", "study.", "Most", "importantly,", "the", "above", "differences", "may", "also", "be", "explained", "by", "underlying", "differences", "in", "genetic", "background", "between", "Chinese", "and", "Western", "populations", "0.9%", "23.5%", ")", "complied", "with", "the", "revised", "Bethesda", "standard.", "Ninety-one", "patients", "(7.4%)", "were", "MSI", "carriers,", "but", "only", "11", "patients", "(0.9%)", "had", "germline", "mutations", "of", "MSH2", "or", "MLH1.", "This", "means", "that", "among", "this", "group,", "only", "0.9%", "of", "patients", "could", "be", "diagnosed", "as", "HNPCC.", "In", "a", "study", "by", "Yearsley", "et", "al.", "[14],", "out", "of", "482", "US", "patients", "with", "colorectal", "cancers,", "87", "patients", "(18%)", "were", "MSI", "carriers", "and", "only", "12", "cases", "(2.5%)", "had", "MMR", "gene", "germline", "mutations.", "These", "results", "may", "be", "explained", "by", "different", "case", "selections", "and", "sensitivity", "of", "the", "tests", "used.", "On", "the", "other", "hand,", "in", "their", "study", "of", "HNPCC", "related", "tumors", "in", "young", "patients", "(<50", "years", "old),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers,", "the", "MLH1", "hypermethylation", "occurred", "in", "89%", "of", "patients.", "Bettstetter", "et", "al.", "[20]", "showed", "that", "all", "sporadic", "MSI-H", "CRCs", "were", "hypermethylated", "at", "the", "MLH1", "promoter.", "These", "results", "were", "similar", "to", "ours.", "Fourteen", "out", "of", "16", "MLH1", "negatively", "staining", "CRCs", "were", "hypermethylated", "at", "the", "MLH1promoter.", "Mutation", "analysis", "revealed", "that", "8", "patients", "(23.5%)", "had", "MMR", "gene", "germline", "mutations", "out", "of", "34", "MSI", "patients.", "Five", "patients", "had", "MSH2", "mutations", "and", "3", "had", "MSH6", "mutations,", "while", "no", "MLH1", "mutation", "was", "found.", "There", "were", "2", "and", "6", "patients", "who", "had", "mutations", "in", "MSH2", "and", "MSH6", "in", "the", "MSI-L", "and", "MSI-H", "groups,", "respectively.", "Yearsley", "et", "al.", "[15],", "in", "their", "study", "of", "87", "patients", "with", "MSI", "colorectal", "cancers,", "found", "12", "patients", "(13.8%)", "with", "MLH1", "and", "MSH2", "germline", "mutations.", "Niessen", "et", "al.", "[16],", "however,", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "was", "82%", "in", "the", "young", "age", "group", "(", "<50", "years", "old", "<50", "years", "old", "),", "Niessen", "et", "al.", "[15]", "found", "that", "the", "rate", "of", "MSH2,", "MSH6", "and", "MLH1", "germline", "mutations", "in", "MSI", "carriers", "was", "82%.", "In", "our", "146", "patients", "with", "colorectal", "cancers,", "34", "patients", "(23.3%)", "had", "MSI", "colorectal", "cancer.", "This", "is", "comparable", "to", "the", "studies", "by", "Pinol", "et", "al.", "[13]", "and", "Yearsley", "et", "al.", "[16].", "Wong", "et", "al.", "[17]", "showed", "that", "in", "the", "case", "of", "sporadic", "endometrial", "carcinoma,", "MSI", "endometrial", "carcinoma", "accounted", "for", "26%", "of", "patients.", "Our", "results", "showed", "that", "there", "were", "15", "(10.3%)", "CRCs", "with", "MSI-L", "and", "19", "(13.0%)", "CRCs", "with", "MSL-H,", "respectively.", "Lamberti", "et", "al.", "[18]", "reported", "that", "MSI-L", "and", "MSI-H", "accounted", "for", "6%", "and", "17%,", "respectively,", "of", "German", "patients.", "These", "results", "are", "similar", "to", "ours.", "Unexpectedly,", "in", "the", "present", "study,", "the", "age", "of", "patients", "with", "MSS", "colorectal", "cancers", "(60", "yrs)", "was", "similar", "to", "the", "age", "of", "patients", "with", "MSI-H", "(61", "yrs).", "In", "contrast,", "the", "average", "age", "of", "patients", "with", "MSI-L", "colorectal", "cancer", "was", "71,", "which", "was", "quite", "different", "from", "the", "reports", "of", "other", "research", "groups", "[13,15,18].", "In", "a", "study", "of", "1263", "patients", "with", "colorectal", "cancers,", "Benatti", "et", "al.", "[19]", "found", "that", "those", "who", "were", "MSI", "carriers", "tended", "to", "have", "mucinous", "and", "right", "colonic", "tumours.", "Noda", "et", "al.", "[20]", "also", "found", "that", "MSI", " ", "carriers", "have", "more", "right", "colonic", "tumors.", "However,", "in", "our", "study,", "tumors", "in", "the", "MSI", "group", "were", "most", "commonly", "located", "at", "the", "rectum,", "and", "mucinous", "carcinoma", "was", "not", "the", "most", "common", "pathological", "type,", "as", "it", "only", "accounted", "for", "29%.", "Interestingly,", "patients", "in", "our", "MSI-L", "group", "were", "older", "than", "the", "MSS", "group.", "The", "reason", "for", "these", "findings", "is", "uncertain.", "Bettstetter", "et", "al.", "[20]", "reported", "that", "the", "average", "age", "of", "MSI", "CRCs", "with", "MLH1", "negative", "staining", "was", "80", "yrs,", "which", "was", "similar", "to", "our", "results.", "Most", "of", "these", "MSI", "CRCs", "were", "caused", "by", "MLH1", "promoter", "hypermethylation.", "In", "our", "group,", "out", "of", "34", "MSI", "CRCs,", "19", "CRCs", "(55.9%)", "were", "hypermethylated", "at", "the", "MLH1", "promoter,", "which", "accounted", "for", "73.7%", "of", "MSI-H", "CRCs", "and", "33.3%", "of", "MSI", "CRCs.", "Anacleto", "et", "al.", "[21]", "reported", "that", "8", "out", "of", "15", "MSI", "CRCs", "had", "MLH1", "promoter", "hypermethylation,", "which", "was", "similar", "to", "our", "results.", "Kim", "et", "al.", "[10]", "found", "that", "in", "MSI-H", "gastric", "cancers", ",", "the", "MLH1", "hypermethylation", "sporadic", " ", "colorectal", "cancer", "is", "the", "most", "important", "method", "to", "screen", "HNPCC.", "In", "2004,", "the", "NCI", "recommended", "the", "revised", "Bethesda", "criteria", "as", "a", "HNPCC", "screening", "guideline", "and", "established", "the", "HNPCC", "diagnostic", "procedures.", "These", "guidelines", "stated", "that", "MSI", "should", "firstly", "be", "identified", "in", "colorectal", "tumor", "tissue,", "and", "then", "genetic", "tests", "would", "be", "performed", "to", "confirm", "MMR", "gene", "germline", "mutations", "in", "a", "blood", "sample", "[6]." ]

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[ "Aim" ]

[ 0 ]

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[ "Conclusions" ]

[ 0 ]

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[ "We", "observed", "increased", "expression", "of", "genes", "in", "chromosomal", "region", "12q14.2-12q22", "(see", "Figures", "15,", "16,", "17).", "The", "MDM2", "gene", "at", "12q15", "is", "a", "possible", "target", "of", "this", "misregulation.", "However,", "within", "this", "large", "region", "there", "is", "a", "smaller", "region", "at", "12q21.1-q21.2", "spanning", "eight", "genes", "that", "exhibit", "exceptionally", "high", "expression", "in", "our", "tumor", "samples.", "Among", "these", "is", "LGR5", "alias", "GPR49,", "a", "G-protein", "coupled", "receptor", "that", "has", "large", "leucine-rich", "repeats", "in", "its", "N-terminus.", "We", "could", "confirm", "the", "up-regulation", "of", "GPR49", "NDRGL3", ",", "RPN2", "and", "CTNNBL1.", "Also", "note", "the", "gene", "C20orf110", "alias", "T", "P53I", "ITCH", ",", "DNCL2A,", "ITG4BP,", "C20orf24,", "NDRGL3,", "RPN2", "and", "CTNNBL1.", "Also", "note", "the", "gene", "C20orf110", "alias", "TP53INP2", "which", "is", "down-regulated", "in", "the", "majority", "of", "tumors." ]

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[ "Abstract" ]

[ 0 ]

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[ "Of", "the", "17", "CRC", " ", "patients", "with", "the", "Lys618Ala", "variant,", "two", "had", "MSI", "(11.8%),", "one", "in", "the", "familial", "CRC", "group", "(1/8)", "and", "one", "in", "the", "sporadic", "CRC", "group", "(1/9)." ]

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[ "Tumours", "from", "p.Lys618Ala", "carrier", "cases", "in", "the", "familial", "group", "(seven", "index", "subjects", "and", "one", "relative)", "were", "also", "analysed", "for", "MLH1", "protein", "expression", "using", "immunohistochemistry", "and", "anti-MLH1", "antibodies", "(PharMingen,", "CA,", "USA)", "as", "described", "elsewhere", "[7].", "Tumour", "cells", "were", "judged", "negative", "for", "protein", "expression", "only", "if", "they", "lacked", "staining", "in", "a", "sample", "in", "which", "normal", "colonocytes", "and", "stroma", "cells", "were", "stained.", "If", "no", "immunostaining", "of", "normal", "tissue", "could", "be", "demonstrated,", "the", "results", "were", "considered", "unreliable." ]

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[]

[]

[ "We", "observed", "increased", "expression", "of", "genes", "in", "chromosomal", "region", "12q14.2-12q22", "(see", "Figures", "15,", "16,", "17).", "The", "MDM2", "gene", "at", "12q15", "is", "a", "possible", "target", "of", "this", "misregulation.", "However,", "within", "this", "large", "region", "there", "is", "a", "smaller", "region", "at", "12q21.1-q21.2", "spanning", "eight", "genes", "that", "exhibit", "exceptionally", "high", "expression", "in", "our", "tumor", "samples.", "Among", "these", "is", "LGR5", "alias", "GPR49,", "a", "G-protein", "coupled", "receptor", "that", "has", "large", "leucine-rich", "repeats", "in", "its", "N-terminus.", "We", "could", "confirm", "the", "up-regulation", "of", "GPR49", "in", "CRC", "by", "quantitative", "PCR", "and", "in-situ", "hybridization", "(data", "not", "shown).", "This", "finding", "and", "the", "exceptional", "suitability", "of", "G-protein-coupled", "receptors", "as", "drug", "targets", "make", "the", "LGR5", "TP53INP2", "patients", " ", "with", "consistent", "up-regulation", "in", "two", "genes", "are", "coded", "by", "different", "shades", "of", "gray.", "Dark", "squared", "regions", "along", "the", "diagonal", "indicate", "coordinated", "regulation", "in", "patient", "subgroups.", "Note,", "that", "many", "more", "patients", " ", "show", "up-regulation", "as", "indicated", "by", "dark", "spots", "in", "this", "plot", "than", "down-regulation", "as", "indicated", "by", "dark", "spots", "in", "Figure", "14.", "The", "known", "most", "frequently", "up-regulated", "genes", "in", "this", "region", "are", "EIF2S2,", "AHCY,", "ITCH,", "DNCL2A,", "ITG4BP,", "C20orf24,", "NDRGL3,", "RPN2", "and", "CTNNBL1.", "Also", "note", "the", "gene", "C20orf110", "alias", "TP53INP2", "which", "is", "down-regulated", "in", "the", "majority", "of", "tumors." ]

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[ "Non-dysplastic", "serrated", "polyps:", "HP", "and", "SSA" ]

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[ "Allelic", "and", "genotypic", "frequencies", "and", "Hardy-Weinberg", "equilibrium" ]

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[ "Pedigree", "showing", "HNPCC", "family.", "An", "arrow", "indicates", "the", "male", "index", "patient", "(III:3)", "diagnosed", "with", "colorectal", "adenocarcinoma", "at", "the", "age", "of", "23", "years.", "Family", "members", "suffering", "from", "a", "malignancy", "are", "indicated", "by", "a", "shaded", "circle", "or", "square.", "The", "age,", "type", "of", "malignancy,", "as", "well", "as", "the", "generation", "(roman", "figures),", "are", "described", "below", "the", "indicated", "patient.", "The", "family", "fulfill", "the", "Amsterdam-I", "criteria", "with", "presence", "of", "extracolonic", "tumors", "in", "the", "extended", "pedigree,", "having", "more", "than", "three", "carcinomas", "of", "colon", "(C)", "or", "ovary", "(O)", "in", "the", "affected", "members.", "The", "syndrome", "is", "present", "in", "all", "three", "generations", "(I-III)", "and", "three", "family", "members", "are", "younger", "than", "50", "years", "(III:3,", "II:1", "and", "I:3).", "At", "the", "moment", "of", "the", "study", "the", "proband's", "mother", "(II-5)", "was", "an", "unaffected", "carrier,", "but", "two", "years", "later", "she", "developed", "an", "endometrial", "(E)", "adenocarcinoma." ]

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[ "An", "epigenetic", "mechanism", "may", "help", "explain", "why", "sporadic", "MSI+", "cancers", "require", "more", "than", "one", "additional", "somatic", "alteration", "relative", "to", "HNPCC", "cancers.", "Inactivation", "of", "the", "normal", "MMR", "allele", "occurs", "through", "mutation", "(usually", "LOH", "[15])", "in", "HNPCC", "whereas", "MMR", "loss", "in", "sporadic", "MSI+", "cancers", "is", "associated", "with", "MLH1", "promoter", "methylation", "[16,17].", "CpG", "islands", "may", "be", "\"protected\"", "from", "methylation", "because", "most", "are", "unmethylated", "at", "birth", "and", "usually", "remain", "unmethylated", "throughout", "life", "[18].", "Epigenetic", "MLH1", "inactivation", "may", "require", "at", "least", "two", "cis", "acting", "somatic", "alterations---loss", "of", "a", "mechanism", "that", "normally", "prevents", "methylation,", "followed", "by", "the", "accumulation", "of", "methylation", "at", "sufficient", "numbers", "of", "CpG", "sites", "to", "silence", "expression." ]

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[]

[]

[ "Mutation-detection", "frequency" ]

[ 0, 0 ]

[ "Tumours", "from", "p.Lys618Ala", "carrier", "cases", "in", "the", "familial", "group", "(seven", "index", "subjects", "and", "one", "relative)", "were", "also", "analysed", "for", "MLH1", "protein", "expression", "using", "immunohistochemistry", "and", "anti-MLH1", "antibodies", "(PharMingen,", "CA,", "USA)", "as", "described", "elsewhere", "[7].", "Tumour", "cells", "were", "judged", "negative", "for", "protein", "expression", "only", "if", "they", "lacked", "staining", "in", "a", "sample", "in", "which", "normal", "colonocytes", "and", "stroma", "cells", "were", "stained.", "If", "no", "immunostaining", "of", "normal", "tissue", "could", "be", "demonstrated,", "the", "results", "were", "considered", "unreliable." ]

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[ "APC", "mutational", "mosaicism", "could", "be", "a", "reason", "for", "the", "quite", "large", "number", "of", "de", "novo", "or", "sporadic", "FAP", "cases", "that", "exist", "[23-25,40].", "In", "the", "family", "of", "C107", "the", "mutation", "has", "not", "been", "passed", "on", "to", "the", "offspring", "of", "the", "patient", "and,", "thus,", "this", "appears", "to", "be", "a", "sporadic", "case,", "but,", "generally,", "the", "existence", "of", "mosaicism", "is", "a", "risk", "of", "error", "in", "predictive", "diagnosis", "in", "FAP/AFAP", "families", "[43].", "In", "the", "initial", "stages,", "the", "molecular", "screening", "procedure", "of", "FAP/AFAP", "patients", "uses", "mainly", "PCR-based", "methods", "for", "analysis", "of", "the", "APC", "gene", "in", "DNA", "from", "isolated", "blood", "samples.", "Therefore,", "the", "chances", "of", "detecting", "pathogenic", "low-frequency", "APC", "mutations", "that", "are", "present", "only", "in", "a", "small", "fraction", "of", "the", "peripheral", "blood", "cells", "or", "only", "in", "the", "colon", "are", "poor.", "Approximately", "25%", "of", "neurofibromatosis", "type", "2", "(NF2)", "patients", "have", "been", "shown", "to", "be", "cases", "of", "mosaicism", "[44].", "When", "investigating", "NF2", "mutational", "mosaicism", "APC", " ", "mutations", "that", "are", "present", "only", "in", "a", "small", "fraction", "of", "the", "peripheral", "blood", "cells", "or", "only", "in", "the", "colon", "are", "poor.", "Approximately", "25%", "of", "neurofibromatosis", "type", "2", "(NF2)", "patients", "have", "been", "shown", "to", "be", "cases", "of", "mosaicism", "[44].", "When", "investigating", "NF2", "mutational", "mosaicism,", "the", "search", "for", "constitutional", "mutations", "is", "preferably", "carried", "out", "initially", "in", "tumor", "cells.", "Detected", "mutations", "could", "subsequently", "be", "verified", "in", "blood", "leukocyte", "samples.", "However,", "this", "approach", "would", "not", "be", "applicable", "for", "FAP", "mosaisicm", "as", "somatic", "APC", "blood", "APC", " ", "mutational", "mosaicism", "could", "be", "a", "reason", "for", "the", "quite", "large", "number", "of", "de", "novo", "or", "sporadic", "FAP", "cases", "that", "exist", "[23-25,40].", "In", "the", "family", "of", "C107", "the", "mutation", "has", "not", "been", "passed", "on", "to", "the", "offspring", "of", "the", "patient", "and,", "thus,", "this", "appears", "to", "be", "a", "sporadic", "case,", "but,", "generally,", "the", "existence", "of", "mosaicism", "is", "a", "risk", "of", "error", "in", "predictive", "diagnosis", "in", "FAP/AFAP", "families", "[43].", "In", "the", "initial", "stages,", "the", "molecular", "screening", "procedure", "of", "FAP/AFAP", "patients", "uses", "mainly", "PCR-based", "methods", "for", "analysis", "of", "the", "APC", " ", "gene", "in", "DNA", "from", "isolated", "blood", "samples.", "Therefore,", "the", "chances", "of", "detecting", "pathogenic", "low-frequency", "APC", "mutations", "that", "are", "present", "only", "in", "a", "small", "fraction", "of", "the", "peripheral", "blood", "cells", "or", "only", "in", "the", "colon", "are", "poor.", "Approximately", "25%", "of", "neurofibromatosis", "type", "2", "(NF2)", "patients", "have", "been", "shown", "to", "be", "cases", "of", "mosaicism", "[44].", "When", "investigating", "NF2", "mutational", "mosaicism,", "the", "search", "for", "constitutional", "mutations", "is", "preferably", "carried", "out", "initially", "in", "tumor", "cells.", "Detected", "mutations", "could", "subsequently", "be", "verified", "in", "blood", "leukocyte", "samples.", "However,", "this", "approach", "would", "not", "be", "applicable", "for", "FAP", "mosaisicm", "as", "somatic", "APC", "mutations", "are", "frequently", "found", "in", "tumors." ]

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[ "Results", "of", "genotyping", "for", "the", "p.Lys618Ala", "variant", "using", "the", "iPLEX", "Sequenom", "(A)", "and", "sequencing", "(B)", "methods." ]

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[ "Three", "patients", "(C107,", "C257,", "and", "C505),", "negative", "for", "mutations", "in", "APC,", "were", "reported", "as", "de", "novo", "cases", "with", "no", "known", "family", "history", "of", "FAP.", "These", "patients", "where", "all", "screened", "for", "APC", "mutations", "present", "as", "low-frequency", "alleles", "using", "SSCP/HD.", "We", "did", "not", "detect", "any", "signs", "of", "low-frequency", "mutations", "in", "patients", "C257", "and", "C505.", "However,", "in", "patient", "C107,", "aberrant", "bands,", "possibly", "originating", "from", "formation", "of", "heteroduplexes,", "was", "detected", "by", "SSCP/HD", "in", "a", "very", "low", "fraction", "of", "her", "blood", "lymphocytes.", "The", "c.2700_2701delTC", "mutation,", "which", "results", "in", "frame", "shift", "at", "codon", "900,", "was", "found", "by", "sequencing", "of", "the", "aberrant", "bands", "excised", "from", "the", "SSCP/HD", "gel", "(Figure", "2A).", "The", "mutation", "was", "detected", "in", "approximately", "one-third", "of", "the", "analyzed", "tumor-derived", "cells", "extracted", "from", "paraffin-embedded", "tissue", "by", "DNA", "sequencing", "(Figure", "2B).", "The", "mutation", "was", "not", "detectable", "at", "all", "in", "the", "sequence", "determination", "of", "DNA", "extracted", "from", "blood", "lymphocytes", "from", "the", "patient", "(Figure", "2C)." ]

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[ "The", "relation", "between", "MMR", "deficiency", "and", "platinum-drug", "resistance", "has", "been", "investigated", "in", "only", "a", "few", "in", "vivo", "studies.", "Similarly", "to", "our", "result,", "no", "MSI", "was", "detected", "by", "Mesquita", "et", "al.", "[18]", "who", "studied", "34", "ovarian", "carcinomas", "of", "which", "seven", "did", "not", "respond", "to", "cisplatin/paclitaxel", "therapy.", "So", "the", "resistance", "seen", "in", "these", "seven", "nonresponding", "patients", "was", "also", "not", "associated", "with", "MMR", "seven", "serous", "clear", "cell", " ", "and", "serous", "adenocarcinoma", "adenocarcinoma", "endometrioid", "mucinous", "carcinoma", " ", "tissues", "analyzed", "(Table", "2).", "This", "difference", "in", "the", "distribution", "could", "be", "a", "cause", "for", "the", "wide", "range", "in", "the", "MSI", "frequency", "especially", "since", "it", "has", "been", "suggested", "that", "certain", "histological", "types", "have", "a", "higher", "frequency", "of", "MSI.", "To", "determine", "whether", "there", "is", "a", "relation", "between", "histology", "and", "MSI", "within", "these", "studies,", "we", "looked", "at", "the", "frequency", "of", "MSI", "per", "histological", "type", "for", "the", "628", "patients", "with", "known", "histology", "(Table", "2).", "The", "summary", "of", "these", "studies", "suggests", "that", "the", "frequency", "of", "MSI", "is", "higher", "in", "the", "mucinous", "and", "endometrioid", "adenocarcinoma", "compared", "to", "clear", "cell", "and", "serous", "adenocarcinoma", "(the", "overall", "frequencies", "of", "MSI", "were", "22%,", "16%,", "9%", "and", "8%,", "respectively)", "(Table", "2).", "We", "hypothesize", "that", "mucinous", "and", "endometrioid", "histology", "might", "be", "prone", "to", "a", "higher", "MSI", "frequency", "since", "sporadic", "endometrial", "carcinoma,", "which", "is", "closely", "related", "to", "endometrioid", "ovarian", "cancer,", "has", "a", "MSI", "frequency", "of", "20–30%", "[49-51]", "and", "MSI", "is", "almost", "universal", "present", "in", "the", "colorectal", "tumors", "of", "the", "hereditary", "nonpolyposis", "colon", "cancer", "(HNPCC)", "syndrome", "which", "all", "have", "a", "mucinous", "histological", "type.", "Therefore,", "the", "different", "histology's", "of", "the", "ovarian", "carcinomas", "included", "in", "the", "several", "studies", "seems", "to", "be", "a", "plausible", "cause", "for", "the", "wide", "range", "in", "MSI", "frequency", "reported", "in", "these", "studies." ]

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[ "The", "adenomas", "in", "this", "study", "were", "grouped", "as", "TAs", "<", " ", "10", "mm,", "TAs", ">", " ", "10", "mm", "and", "TVAs/VAs.", "Overall,", "KRAS", "mutation", "occurred", "in", "26.5%", "of", "adenomas", "while", "BRAF", "mutation", "was", "detected", "in", "only", "4.8%.", "Three", "of", "the", "four", "BRAF", "mutations", "occurred", "in", "adenomas", "that", "also", "had", "KRAS", "mutation.", "It", "is", "well", "established", "that", "BRAF", "and", "KRAS", "mutation", "rarely", "occur", "in", "the", "same", "colorectal", "neoplasm.12,16,30", "Furthermore,", "BRAF", "mutations", "are", "much", "more", "typical", "of", "serrated", "polyps", "than", "adenomas.14,31", "The", "assay", "for", "BRAF", "mutation", "used", "in", "this", "study", "was", "highly", "sensitive", "and", "it", "is", "possible", "that", "the", "mutation", "was", "being", "identified", "in", "normal", "mucosa", "included", "with", "the", "polyp.", "KRAS", "mutation", "may", "occur", "within", "apparently", "normal", " ", "colorectal", "mucosa", "and", "the", "same", "could", "apply", "to", "BRAF.32", "Therefore,", "the", "finding", "of", "BRAF", "mutation", "in", "a", "small", "subset", "of", "adenomas", "could", "be", "spurious", "and", "the", "true", "incidence", "of", "BRAF", "mutation", "in", "colorectal", "adenomas", "could", "be", "lower", "than", "4.8%.", "BRAF", "mutation", "frequencies", "of", "0%14", "and", "3%31", "have", "been", "reported", "in", "other", "series", "of", "colorectal", "adenomas." ]

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[ "dysplastic", "serrated", "polyps:", "MP", "and", "SA" ]

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[ "To", "establish", "and", "explain", "the", "pattern", "of", "molecular", "signatures", "across", "colorectal", "polyps." ]

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[ "The", "early", "to", "intermediate", "stages", "of", "the", "majority", "of", "colorectal", "tumours", "are", "thought", "to", "be", "driven", "by", "aberrations", "in", "the", "Wnt", "(APC,", "CTNNB1)", "and", "Ras", "(K-ras)", "pathways.", "A", "smaller", "proportion", "of", "cancers", "shows", "mismatch", "repair", "deficiency.", "The", "aim", "of", "this", "study", "was", "to", "analyse", "the", "co-occurrence", "of", "these", "genetic", "alterations", "in", "relation", "to", "tumour", "and", "patient", "characteristics." ]

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[ "Results" ]

[ 0 ]

[ "Statistics", "on", "expression", "imbalances", "across", "human", "chromosomes." ]

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[ "Results" ]

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[ "Hierarchical", "clustering", "of", "samples", "from", "colorectal", "tumors", "and", "normal", "colon", "epithelia.", "On", "the", "right,", "you", "find", "the", "chromosomal", "localization", "of", "the", "genes", "and", "the", "official", "HUGO", "symbol", "or", "prospective", "Affymetrix", "cluster", "ID.", "On", "the", "top,", "the", "binary", "tree", "of", "tissue", "samples", "based", "on", "gene", "expression", "is", "given.", "The", "tissue", "denominators", "either", "contain", "TR", "for", "tumor", "or", "E", "for", "epithelium", "and", "a", "code", "reflecting", "the", "identity", "of", "each", "patient.", "In", "the", "center,", "the", "expression", "values", "after", "normalization", "have", "been", "color-coded:", "light", "blue", "means", "high", "expression,", "black", "means", "low", "(or", "no)", "expression.", "Note", "that", "only", "a", "representative", "fraction", "of", "the", "514", "genes", "is", "visualized", "here", "(white", "bars", "replace", "some", "portions", "of", "original", "heat", "map).", "The", "right", "cluster", "contains", "only", "samples", "from", "normal", "colon", "epithelia,", "the", "left", "cluster", "is", "composed", "primarily", "of", "tumors", "normal", " ", "tissues", "mainly", "clustered", "together", "with", "matching", "tumor", "samples", "from", "same", "patients.", "This", "suggests", "that", "coalescence", "between", "tumor", "and", "normal", "samples", "from", "the", "same", "patients", "could", "be", "due", "to", "patient-specific", "gene", "expression", "characteristics.", "As", "the", "majority", "of", "normal", "samples", "could", "be", "clearly", "separated", "from", "tumors,", "we", "concluded", "that", "our", "data", "set", "is", "well", "suited", "to", "explore", "differences", "in", "gene", "expression", "between", "normal", "and", "tumor", "cells", "of", "colorectal", "origin." ]

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[ "Results" ]

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