Datasets:

Brizape

/

Variome_split_0404_dev

like 0

[ "Next,", "we", "compared", "the", "patient", "and", "tumour", "characteristics", "of", "tumours", "harbouring", "a", "truncating", "APC", "and/or", "an", "activating", "K-ras", "mutation", "to", "those", "of", "tumours", "without", "hMLH1", "expression,", "and", "these", "results", "are", "presented", "in", "table", "4.", "Patients", "harbouring", "hMLH1", "deficient", "tumours", "were", "slightly", "older", "when", "diagnosed", "with", "colorectal", "cancer", "(69.3", "yr", "(68.0–70.5)", "versus", "67.8", "(67.4–68.3),", "P", "=", "0.03),", "were", "relatively", "less", "frequently", "men", "(40%", "versus", "58%", "rectosigmoid", " ", "and", "rectum", "more", "frequently", "harboured", "truncating", "APC", "mutations", "when", "compared", "to", "colon", "tumours", "(P", "=", "0.001),", "as", "shown", "in", "table", "3.", "Rectosigmoid", "and", "rectal", "tumours", "have", "a", "relatively", "higher", "frequency", "of", "K-ras", "mutations", "in", "codons", "12", "and", "13", "when", "compared", "to", "colon", "tumours", "(P", "=", "0.05)", "(Table", "3).", "Nine", "per", "cent", "of", "tumours", "showed", "hMLH1", "deficiency,", "as", "determined", "by", "immunohistochemistry", "(Figure", "2).", "Tumours", "lacking", "hMLH1", "expression", "occur", "almost", "exclusively", "in", "the", "proximal", "colon", "(P", "<", "0.001)", "and", "relatively", "more", "frequently", "show", "poor", "differentiation", "or", "are", "undifferentiated", "(P", "<", "0.001)", "when", "compared", "to", "tumours", "with", "hMLH1", "expression", "(Table", "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, 9, 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, 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 ]

[ "Serrated", "polyps", "with", "dysplasia,", "i.e.", "MPs", "and", "SAs,", "together", "comprised", "only", "2%", "of", "the", "overall", "consecutive", "series", "of", "1250", "polyps.", "While", "mutation", "of", "KRAS", "and", "BRAF", "was", "associated", "with", "conventional", "adenoma", "and", "SSA,", "respectively", "(see", "above),", "BRAF", "and", "KRAS", "mutation", "occurred", "with", "similar", "frequency", "in", "both", "MPs", "(40%", "and", "50%,", "respectively)", "and", "SAs", "(33%", "and", "27%,", "respectively).", "In", "the", "literature,", "the", "frequency", "of", "BRAF", "and", "KRAS", "mutation", "in", "MP", "SSAs", " ", "(81%).", "Previous", "reports", "have", "shown", "very", "similar", "results", "for", "BRAF", "mutation", "in", "SSA,16", "but", "higher", "frequencies", "of", "KRAS", "mutation", "and", "lower", "frequencies", "of", "BRAF", "mutation", "KRAS", "SSA", ",16", "but", "higher", "frequencies", "of", "KRAS", "mutation", "and", "lower", "frequencies", "of", "BRAF", "mutation", "in", "HPs.12,16,38", "As", "mentioned", "in", "Materials", "and", "methods,", "there", "had", "been", "selection", "of", "larger", "HPs", "in", "an", "earlier", "cell", "kinetic", "study", "involving", "the", "same", "material.", "Large", "HPs", "are", "more", "likely", "to", "include", "the", "subset", "described", "as", "‘microvesicular’,", "in", "which", "the", "columnar", "cells", "contain", "apical", "mucin", "droplets", "within", "small", "vesicles", "while", "goblet", "cells", "are", "rendered", "inconspicuous.25BRAF", "mutation", "occurs", "more", "frequently", "in", "the", "microvesicular", "variant", "of", "HP.16", "By", "contrast,", "KRAS", "mutation", "occurs", "much", "more", "commonly", "in", "the", "goblet", "cell", "variant", "of", "HP,", "which", "is", "usually", "small,", "located", "in", "the", "left", "colon", "or", "rectum", "and", "deviates", "minimally", "from", "normal", "colorectal", "mucosa", "in", "terms", "of", "differentiation", "and", "architecture.16,25", "The", "latter", "were", "under-represented", "in", "this", "series", "(details", "not", "shown)." ]

[ 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, 9, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 5, 21, 1, 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, 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 ]

[ "Evolutionary", "conservation,", "examined", "by", "alignment", "of", "sequences", "of", "homologous", "proteins", "for", "several", "species", "(fig.", "4),", "suggests", "a", "functional", "relevance", "for", "the", "amino", "acid", "involved.", "This", "is", "also", "supported", "by", "the", "mutator", "phenotype", "described", "for", "Pro640Leu", "mother", "hMLH1", " ", "genes", "was", "indicated,", "detecting", "a", "novel", "germline", "mutation,", "a", "c.1864C>A", "transversion", "in", "exon", "12", "of", "hMSH2", "hMSH2", " ", "and", "hMLH1", "genes", "was", "indicated,", "detecting", "a", "novel", "germline", "mutation,", "a", "c.1864C>A", "transversion", "in", "exon", "12", "of", "hMSH2", "gene", "at", "the", "heterozygous", "state", "(fig.", "3)", "leading", "to", "a", "proline", "622", "to", "threonine", "(p.Pro622Thr)", "amino", "acid", "substitution.", "This", "is", "the", "second", "report", "involving", "the", "622", "codon", "in", "HNPCC", "[13]." ]

[ 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, 5, 13, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 21, 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 ]

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

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

[ "In", "a", "group", "of", "656", "unselected", "sporadic", "colorectal", "cancer", "patients,", "aberrations", "in", "the", "APC,", "K-ras,", "CTNNB1", "genes,", "and", "expression", "of", "hMLH1", "were", "investigated.", "Additionally,", "tumours", "were", "divided", "in", "groups", "based", "on", "molecular", "features", "and", "compared", "with", "respect", "to", "patient's", "age", "at", "diagnosis,", "sex,", "family", "history", "of", "colorectal", "cancer,", "tumour", "sub-localisation,", "Dukes'", "stage", "and", "differentiation." ]

[ 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 ]

[ "Aim" ]

[ 0 ]

[ "The", "method", "for", "mutation", "analysis", "of", "the", "APC", " ", "mutation", "cluster", "region", "and", "exon", "1", "of", "K-ras", "is", "based", "on", "nested", "amplification", "and", "direct", "sequencing", "of", "purified", "PCR", "fragments,", "a", "highly", "sensitive", "method.", "Since", "no", "screening", "step", "was", "performed", "prior", "to", "the", "sequencing", "of", "the", "gene", "fragments,", "it", "is", "unlikely", "that", "mutations", "would", "have", "escaped", "detection.", "The", "reproducibility", "of", "the", "applied", "assays", "was", "good,", "with", "a", "reproducibility", "of", "85%", "and", "88%", "for", "APC", " ", "and", "K-ras,", "respectively.", "Arguably,", "this", "indicates", "the", "extent", "of", "heterogeneity", "present", "in", "the", "tumour", "samples." ]

[ 0, 0, 0, 0, 0, 0, 0, 21, 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, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "In", "the", "present", "case,", "we", "overcame", "the", "difficulty", "of", "having", "a", "proband", "post-mortem", "non-tumor", "tissue", "sample", "for", "MSI", "testing", "by", "studying", "the", "alleles", "carried", "by", "his", "progenitors.", "Microsatellites", "are", "inherited", "according", "to", "Mendelian", "rules", "like", "any", "other", "genetic", "markers.", "Each", "progenitor", "pass", "one", "of", "its", "two", "alleles", "to", "its", "offspring", "and", "by", "definition,", "the", "alleles", "present", "in", "the", "proband's", " ", "tumor", " ", "tissue", "but", "absent", "in", "his", "progenitors", "are", "the", "result", "of", "somatic", "mutation." ]

[ 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, 9, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "There", "were", "no", "significant", "associations", "in", "the", "case-control", "and", "case-case", "studies", "(80%", "detection", "power,", "OR", "=", "3.0;", "two-sided", "test,", "alpha", "level", "=", "5%)", "(Table", "2)", "and", "no", "statistically", "significant", "associations", "when", "the", "OR", "was", "adjusted", "for", "age", "and", "sex." ]

[ 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 ]

[ "In", "this", "study,", "the", "occurrence", "of", "mutations", "in", "the", "APC,", "CTNNB1", "and", "K-ras", "genes", "as", "well", "as", "expression", "of", "the", "hMLH1", "protein", "in", "tumour", "tissue", "of", "656", "sporadic", "colorectal", "cancer", "cases", "were", "investigated.", "The", "occurrence", "of", "mutations", "in", "the", "CTNNB1", "gene,", "which", "codes", "for", "β-catenin,", "was", "rare:", "only", "five", "of", "464", "tumours", "analysed", "were", "found", "to", "have", "a", "mutation", "at", "one", "of", "the", "phosphorylation", "sites", "in", "exon", "3.", "Truncating", "mutations", "in", "APC", "and", "activating", "mutations", "in", "K-ras", "appeared", "to", "occur", "at", "similar", "frequencies.", "Although", "tumours", "harbouring", "both", "mutations", "were", "relatively", "rare,", "mutations", "in", "APC", "and", "K-ras", "seemed", "to", "occur", "co-dependently.", "Nine", "percent", "of", "all", "tumours", "(58/656)", "lacked", "hMLH1", "expression,", "and", "in", "these", "tumours", "almost", "no", "APC", "or", "K-ras", "mutations", "was", "detected.", "Patients", "harbouring", "a", "tumour", "with", "absent", "hMLH1", "expression", "were", "older,", "more", "often", "women,", "more", "often", "had", "proximal", "colon", "tumours", "that", "showed", "poorer", "differentiation", "when", "compared", "to", "patients", "who", "harboured", "a", "tumour", "with", "an", "APC", "and/or", "K-ras", "mutation." ]

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

[ "DNA", "from", "blood", "cells", "(familial", "cancer", "cases", "and", "controls)", "or", "colorectal", "mucosa", "of", "normal", "appearance", "(sporadic", "cases)", "was", "used", "for", "the", "c.1852_1853AA>GC", "variant", "genotyping.", "This", "was", "assessed", "using", "the", "iPLEX", "Gold", "method", "(Sequenom,", "CA,", "USA),", "in", "which", "single-base", "extension", "and", "MALDI-TOF", "technology", "are", "employed", "for", "allelic", "discrimination.", "These", "experiments", "were", "carried", "out", "at", "the", "Centro", "Español", "de", "Genotipado", "(CEGEN)", "genotyping", "platform", "facilities.", "Quality", "control", "for", "genotyping", "was", "conducted", "by", "direct", "sequencing", "of", "familial", "cancer", "subjects", "who", "underwent", "genetic", "analysis", "for", "MLH1", "(49/1034,", "4.7%", "CRC", " ", "cases" ]

[ 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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 1, 0, 0 ]

[ "Conclusion" ]

[ 0 ]

[ "Methods" ]

[ 0 ]

[ "Conclusion" ]

[ 0 ]

[ "Results" ]

[ 0 ]

[ "Note:", "no", "result", "for", "KRAS", "in", "one", "sessile", "serrated", "adenoma", "(SSA)", "and", "one", "tubular", "adenoma", "(TA)", "or", "for", "BRAF", "in", "one", "TA.", "MGMT", "immunstaining", "not", "performed", "in", "15", "polyps", "(seven", "HPs,", "one", "SSA,", "one", "MP", "and", "six", "TAs)." ]

[ 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 ]

[ "Tumour", "material", "of", "colorectal", "cancer", "patients", "was", "collected", "after", "approval", "by", "the", "Ethical", "Review", "Board", "of", "Maastricht", "University,", "PALGA", "and", "the", "NCR.", "Tissue", "samples", "from", "819", "colorectal", "cancer", "patients", "were", "localized", "in", "54", "pathology", "laboratories", "throughout", "the", "Netherlands.", "Forty-four", "(5%)", "tumour", "tissue", "samples", " ", "could", "not", "be", "retrieved", "from", "the", "pathology", "archives.", "Of", "775", "available", "tissue", "samples", ",", "737", "(95%)", "contained", "sufficient", "tumour", "material", "for", "molecular", "analyses.", "Tissue", "sections", "were", "cut", "from", "each", "sample,", "which", "were", "used", "for", "DNA", "isolation", "and", "immunohistochemical", "analysis." ]

[ 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, 9, 10, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 10, 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 ]

[ "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." ]

[ 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, 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 ]

[ "Individual", "chromosomal", "islands", "with", "gain", "of", "expression" ]

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

[ "No", "MMR", "inactivation", "was", "detected", "in", "75", "ovarian", "carcinoma", "specimens", "and", "no", "association", "was", "seen", "between", "MMR", "inactivation", "and", "resistance", "in", "the", "ovarian", "cancer", " ", "cell", "lines", "as", "well", "as", "the", "ovarian", "carcinomas.", "In", "the", "discussion,", "the", "results", "were", "compared", "to", "that", "of", "twenty", "similar", "studies", "in", "the", "literature", "including", "in", "total", "1315", "ovarian", "cancer", "patients", " ", "received", "platinum-based", "chemotherapy", "(11", "non-responders,", "34", "responders,", "one", "unknown", "response).", "The", "resistance", "seen", "in", "the", "eleven", "non-responders", "was", "not", "related", "to", "MSI", "and", "therefore", "also", "not", "to", "MMR", "inactivation." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 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, 2, 9, 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 ]

[ "Mutation", "number", "estimates", "with", "respect", "to", "clinical", "stage", "may", "be", "biased", "with", "the", "Finnish", "data", "because", "it", "includes", "only", "specimens", "with", "tissue", "available", "for", "molecular", "analysis.", "Advanced", "cancers", "may", "not", "be", "removed.", "Therefore,", "a", "similar", "analysis", "was", "performed", "on", "a", "population-based", "cancer", "registry", "[10]", "from", "the", "United", "States", "of", "America", "(SEER", "11", "Regs", "Public-Use,", "Nov", "2001", "Sub", "(1992–1999)),", "which", "records", "ages", "and", "stages", "at", "diagnosis", "regardless", "of", "treatment", "(Table", "2).", "The", "average", "age", "at", "diagnosis", "was", "70.5", "years,", "consistent", "with", "an", "estimate", "of", "six", "mutations", "to", "colorectal", "cancer", "for", "the", "108,275", "white", "males", "and", "females", "with", "stage", "data.", "Like", "the", "Finnish", "cancers", "cancers", " ", "obtained", "from", "nine", "large", "regional", "hospitals", "in", "southeastern", "Finland", "[9].", "There", "were", "895", "(87.6%)", "MSI-", "cancers", "and", "127", "(12.4%)", "MSI+", "cancers.", "The", "MSI+", "cancers", "were", "further", "classified", "as", "sporadic", "(N", "=", "98", "or", "9.6%", "of", "all", "cancers)", "or", "HNPCC", "(N", "=", "29", "or", "2.9%", "of", "all", "cancers)", "based", "on", "germline", "MLH1", "or", "MSH2", "mutations", "(Table", "1)." ]

[ 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, 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, 9, 1, 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 ]

[ "Using", "a", "variety", "of", "mutation-detection", "techniques,", "we", "have", "achieved", "a", "100%", "detection", "frequency", "in", "classical", "FAP.", "Probands", "with", "APC", "mutations", "outside", "codon", "1250–1464,", "although", "exhibiting", "a", "less-severe", "phenotype,", "are", "at", "high", "risk", "of", "having", "a", "colorectal", "cancer", "at", "diagnosis", "indicating", "that", "age", "at", "diagnosis", "is", "as", "important", "as", "the", "severity", "of", "the", "disease", "for", "colorectal", "cancer", "cancer", "patients", "." ]

[ 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, 1, 1, 9, 0 ]

[ "Concomitant", "deleterious", "variants", "were", "detected", "in", "two", "of", "the", "families:", "one", "in", "the", "MLH1", "gene", "(c.676C>T;", "p.Arg226X)", "and", "the", "other", "in", "the", "MSH6", "gene", "(c.3013C>T;", "p.Arg1005X).", "Seventeen", "affected", "and", "unaffected", "family", "members", "from", "these", "two", "families", "were", "tested", "for", "the", "pathogenic", "and", "p.Lys618Ala", "variants." ]

[ 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 ]

[ "20q11.22-q11.23" ]

[ 0 ]

[ "Mutation", "frequencies", "for", "both", "KRAS", "(P", "<", "0.0001)", "and", "BRAF", "(P", "<", "0.0001)", "are", "distributed", "differently", "across", "the", "seven", "classes", "of", "polyp", "(see", "Results", "for", "individual", "comparisons).", "Distribution", "of", "MGMT", "loss", "differs", "across", "the", "seven", "classes", "of", "polyp", "(P", "<", "0.001)." ]

[ 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 ]

[ "Pedigree", "for", "Family", "#1", "(CRC:", "Colorectal", "cancer;", "GC:", "Gastric", "cancer;", "DC", ":", "Duodenal", "nephews", "nephews", " ", "(III-6;", "III-7)", "had", "the", "wild", "types", "of", "the", "two", "variants", "(Family", "#1,", "Figure", "2)." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 3, 13, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "No", "MMR", "inactivation", "was", "detected", "in", "75", "ovarian", "carcinoma", "specimens", "and", "no", "association", "was", "seen", "between", "MMR", "inactivation", "and", "resistance", "in", "the", "ovarian", "cancer", "cell", "lines", "ovarian", " ", "cancer", "is", "hindered", "by", "intrinsic", "or", "acquired", "resistance", "to", "platinum-based", "chemotherapy.", "The", "aim", "of", "this", "study", "is", "to", "determine", "the", "frequency", "of", "mismatch", "repair", "(MMR)", "inactivation", "in", "ovarian", " ", "cancer", "and", "its", "association", "with", "resistance", "to", "platinum-based", "chemotherapy." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 10, 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, 3, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "MSI", "is", "an", "important", "phenotype", "of", "MMR", "gene", "mutation.", "In", "1997,", "the", "National", "Cancer", "Institute", "(NCI)", "recommended", "screening", "MSI", "CRCs", "using", "the", "Bethesda", "guidelines", "[5].", "After", "compiling", "evidence", "from", "years", "of", "global", "studies", "and", "follow", "up,", "NCI", "revised", "the", "Bethesda", "guidelines", "in", "2004,", "which", "is", "called", "the", "revised", "Bethesda", "standard", "[6].", "NCI", "recommended", "screening", "of", "HNPCC", "based", "on", "detection", "of", "MSI", "in", "the", "tumor", "and", "loss", "of", "expression", "of", "a", "MMR", "gene", "using", "immunohistochemistry", "(IHC)", "staining", "[6].", "However,", "until", "now,", "there", "has", "been", "no", "research", "about", "the", "applicability", "of", "the", "NCI", "recommendations", "to", "the", "Chinese", "population", "with", "colorectal", "cancers.", "The", "aim", "of", "this", "study", "is", "to", "detect", "and", "study", "MSI", "carrier", "and", "mismatch", "repair", "Chinese", " ", "population", "with", "colorectal", "cancers.", "The", "aim", "of", "this", "study", "is", "to", "detect", "and", "study", "MSI", "carrier", "and", "mismatch", "repair", "(MMR)", "gene", "germline", "mutation", "carriers", "among", "a", "Chinese", "germline", "mutation", "MMR", " ", "gene", "using", "immunohistochemistry", "(IHC)", "staining", "[6].", "However,", "until", "now,", "there", "has", "been", "no", "research", "about", "the", "applicability", "of", "the", "NCI", "recommendations", "to", "the", "Chinese", "population", "with", "colorectal", "cancers.", "The", "aim", "of", "this", "study", "is", "to", "detect", "and", "study", "MSI", "carrier", "and", "mismatch", "repair", "(MMR)", "gene", "germline", "mutation", "carriers", "among", "a", "Chinese", "population", "with", "colorectal", "cancer." ]

[ 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, 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, 21, 22, 25, 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, 25, 5, 6, 21, 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 ]

[ "Concept", "of", "‘fusion’", "pathways", "to", "crc" ]

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

[ "Associations", "between", "BRAF", "mutation", "and", "molecular", "features", "of", "colorectal", "cancer." ]

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

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "With", "respect", "to", "the", "25", "serrated", "polyps", "with", "dysplasia,", "only", "five", "occurred", "in", "the", "proximal", "colon", "(up", "to", "the", "splenic", "flexure).", "Two", "of", "these", "had", "BRAF", "mutation", "(both", "Group", "A)", "and", "two", "had", "KRAS", "mutation", "(both", "Group", "B).", "Seven", "of", "the", "11", "BRAF", "mutations", "occurred", "in", "polyps", "derived", "from", "the", "left", "colon", "or", "rectum", "(remaining", "two", "polyps", "with", "BRAF", "mutation", "from", "site", "unknown).", "The", "three", "Group", "A", "SAs", "with", "KRAS", "KRAS", " ", "mutations", "in", "both", "types", "of", "serrated", "polyp", "indicated", "that", "MPs", "and", "SAs", "might", "be", "heterogeneous", "lesions.", "These", "25", "serrated", "polyps", "with", "dysplasia", "were", "therefore", "grouped", "differently.", "Group", "A", "polyps", "(n", "=", "16)", "included", "a", "non-dysplastic", "serrated", "component", "and/or", "dysplastic", "epithelium", "in", "which", "the", "architectural", "and", "cytological", "changes", "were", "more", "reminiscent", "of", "HP", "than", "adenoma", "(Figure", "1A,B).", "Group", "B", "polyps", "(n", "=", "9)", "comprised", "serrated", "polyps", "in", "which", "the", "epithelial", "dysplasia", "appeared", "adenomatous", "(Figure", "1C,D).", "BRAF", "mutation", "occurred", "in", "10/16", "Group", "A", "polyps", "but", "only", "1/9", "Group", "B", "polyps", "(P", "<", "0.03).", "KRAS", "mutation", "occurred", "in", "only", "3/16", "Group", "A", "polyps", "but", "in", "5/9", "Group", "B", "polyps", "(P", "=", "0.06).", "In", "each", "of", "the", "five", "Group", "B", "polyps", "with", "KRAS", "mutation,", "the", "adenomatous", "component", "showed", "both", "villous", "change", "and", "serration." ]

[ 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, 21, 21, 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, 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 ]

[ "KRAS", "mutation", "occurred", "in", "26.5%", "and", "BRAF", "mutation", "in", "4.8%", "of", "adenomas", "(all", "types)", "(Table", "1)", "(P", "<", "0.0001).", "TVAs/VAs", "were", "more", "likely", "to", "have", "KRAS", "mutation", "(50%)", "than", "TAs", "<", " ", "10", "mm", "(18%)", "(P", "<", "0.004)", "or", "TAS", ">", " ", "10", "mm", "in", "diameter", "(17%)", "(P", "<", "0.02).", "In", "the", "case", "of", "TAs", "there", "was", "a", "trend", "for", "KRAS", "mutation", "BRAF", "34", "of", "188", " ", "polyps", "(18%)", "had", "mutation", "of", "KRAS.", "Twenty-eight", "mutations", "were", "in", "codon", "12", "(20", "G→A,", "seven", "G→T", "and", "one", "G→C)", "and", "six", "mutations", "were", "in", "codon", "13", "(all", "G→A).", "One", "serrated", "adenoma", "had", "two", "KRAS", "mutations", "in", "codon", "12", "(G→T", "at", "position", "35", "and", "T→G", "at", "position", "36).", "BRAF", "mutation", "at", "V600E", "could", "be", "assessed", "in", "all", "polyps", "except", "for", "a", "single", "TA", "<", " ", "10", "mm.", "BRAF", "mutation", "was", "found", "in", "82", "of", "189", "polyps", "(43%).", "BRAF", "and", "KRAS", "mutations", "were", "negatively", "correlated,", "with", "only", "four", "polyps", "having", "both", "mutations", "(two", "TAs,", "one", "TVA", "and", "one", "SSA).", "The", "three", "conventional", "adenomas", "with", "mutations", "of", "both", "BRAF", "and", "KRAS", "were", "among", "only", "four", "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)." ]

[ 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, 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, 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 ]

[ "Background" ]

[ 0 ]

[ "In", "the", "second", "LS", "family,", "the", "index", "subject,", "one", "sister", "and", "one", "brother", "with", "CRC", "(II-5;", "II-6;", "II-7,", "respectively)", "had", "a", "deleterious", "variant", "in", "MSH6", "(c.3013C>T;", "p.Arg1005X)", "but", "did", "not", "have", "the", "p.Lys618Ala", "variant.", "This", "variant", "was", "present", "in", "only", "three", "of", "four", "unaffected", "nephews", "(III-2;", "III-3;", "III-4)", "and", "was", "inherited", "from", "the", "parental", "branch,", "in", "which", "there", "was", "no", "familial", "history", "of", "cancer.", "Individuals", "III-3", "and", "III-4", "inherited", "also", "the", "deleterious", "variant.", "No", "genetic", "testing", "was", "available", "from", "the", "father", "or", "paternal", "relatives", "(Family", "#2,", "Figure", "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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "Unfortunately,", "genetic", "testing", "for", "hereditary", "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." ]

[ 0, 0, 0, 0, 17, 9, 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", "frequency", "of", "variants", "in", "unaffected", "controls", "is", "used", "often", "to", "distinguish", "between", "neutral", "and", "potentially", "deleterious", "variants.", "If", "the", "frequency", "of", "a", "variant", "among", "a", "few", "hundred", "controls", "is", "≥1%,", "it", "is", "highly", "unlikely", "to", "be", "a", "high-risk", "variant.", "In", "such", "cases,", "it", "is", "still", "possible", "that", "the", "variant", "will", "be", "associated", "with", "a", "modest", "risk", "of", "the", "disease", "[3].", "Case-control", "studies", "enable", "quantification", "of", "the", "disease", "risk", "associated", "with", "the", "variant.", "The", "main", "disadvantage", "of", "such", "analyses", "is", "that", "a", "large", "sample", "size", "is", "required", "to", "obtain", "sufficient", "power", "to", "detect", "the", "lower", "risk", "level.", "The", "sample", "size", "required", "is", "related", "inversely", "to", "the", "frequency", "of", "the", "variant", "in", "the", "population.", "The", "sample", "size", "used", "in", "the", "present", "study", "resulted", "in", "80%", "power", "to", "detect", "an", "OR", "of", "3.0", "(two-sided", "test;", "alpha", "level,", "5%).", "The", "frequency", "of", "the", "p.Lys618Ala", "variant", "in", "our", "control", "series", "was", "2.7%", "and", "no", "significant", "differences", "were", "observed", "in", "the", "sporadic", "and", "familial", "groups,", "indicating", "that", "a", "high", "penetrance", "effect", "for", "colorectal", "carcinogenesis", "cancer", " ", "frequently", "fails", "to", "identify", "unambiguous", "deleterious", "variants.", "Erroneous", "classification", "of", "a", "genetic", "variant", "may", "have", "a", "great", "effect", "on", "at-risk", "familial", "who", "undergo", "genetic", "testing", "for", "risk", "prediction", "because", "it", "results", "in", "incorrect", "clinical", "recommendations." ]

[ 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, 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, 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, 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 ]

[ "Frequency", "of", "KRAS", "and", "BRAF", "mutation", "and", "loss", "of", "expression", "of", "O-6-methylguanine", "DNA", "methyltransferase", "(MGMT)", "by", "polyp", "type" ]

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

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "The", "chromosomal", "region", "14q24.3", "has", "been", "implicated", "in", "colorectal", "patients", "patient", " ", "counts", "with", "coordinate", "up-regulation).", "Grayscale", "cross-comparison", "plot", "of", "up-regulation", "patterns", "across", "patients", "(analogous", "to", "Figures", "7,", "10,", "13).", "View", "this", "plot", "in", "conjunction", "with", "Figures", "27", "and", "29." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 3, 9, 9, 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", "χ2", "test", "and", "Cramérs", "V", "test", "were", "used", "to", "estimate", "the", "association", "of", "the", "co-occurrence", "of", "K-ras", "and", "APC", "gene", "mutations.", "Characteristics", "of", "patients", "(age", "at", "diagnosis,", "sex,", "family", "history", "of", "colorectal", "cancer", "hMLH1", "tumours", "hMLH1", " ", "expression", "could", "be", "determined", "in", "724", "of", "737", "patients." ]

[ 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, 21, 9, 21, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "a", "Data", "was", "unavailable", "for", "MSI", "status", "in", "40", "cases,", "methylation", "status", "in", "83", "cases,", "KRAS", "mutation", "in", "26", "cases", "and", "TP53", "mutation", "in", "26", "cases" ]

[ 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 ]

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "In", "the", "statistical", "analysis,", "data", "from", "656", "patients", "for", "whom", "information", "on", "APC", "and", "K-ras", "mutation", "status", "as", "well", "as", "hMLH1", "expression", "was", "complete", "were", "included." ]

[ 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 ]

[ "Screening", "for", "mosaic", "mutations", "in", "the", "three", "APC-", "and", "MUTYH-negative", "patients", "with", "de", "novo", "mutations", "revealed", "the", "c.2700_2701delTC", "mutation", "in", "patient", "C107.", "This", "mutation", "was", "detected", "in", "a", "very", "low", "fraction", "of", "the", "lymphocytes", "and", "was", "only", "detectable", "using", "the", "SSCP/HD", "analysis", "(Figure", "2A).", "Owing", "to", "the", "subtle", "appearance", "of", "this", "mutation", "it", "could", "easily", "have", "been", "overlooked." ]

[ 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 ]

[ "Molecular", "alterations", "that", "are", "characteristic", "of", "the", "serrated", "pathway", "and", "adenoma–carcinoma", "sequence", "can", "co-occur", "in", "a", "minority", "of", "advanced", "colorectal", "polyps", "that", "then", "show", "morphological", "features", "of", "both", "pathways.", "These", "lesions", "account", "for", "only", "2%", "of", "colorectal", "serrated", " ", "polyps", " ", "and", "adenomas:", "concept", "of", "a", "‘fusion’", "pathway", "to", "colorectal", "cancer" ]

[ 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, 3, 17, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "Methods" ]

[ 0 ]

[ "Loss", "of", "expression", "of", "the", "DNA", "repair", "gene", "MGMT", "is", "associated", "with", "methylation", "of", "the", "promoter", "region45,51,52", "and", "the", "latter", "change", "has", "been", "linked", "causatively", "with", "G:C", "to", "A:T", "transition", "mutations", "in", "TP53.53", "In", "the", "present", "study,", "complete", "or", "partial", "loss", "of", "expression", "of", "MGMT", "coincided", "with", "aberrant", "nuclear", "expression", "of", "p53", "in", "three", "serrated", "polyps", "with", "dysplasia", "(Figure", "2),", "but", "not", "in", "the", "single", "tubular", "adenoma", "with", "aberrant", "p53", "expression.", "Only", "one", "previous", "study", "has", "attempted", "to", "correlate", "MGMT", "and", "p53", "expression", "in", "colorectal", "polyps.45", "In", "that", "study,", "4.3%", "of", "adenomas", "showed", "aberrant", "p53", "expression", "but", "none", "had", "loss", "of", "MGMT.", "It", "is", "possible", "that", "the", "link", "between", "MGMT", "silencing", "and", "TP53", "mutation", "is", "more", "evident", "in", "the", "serrated", "pathway", "than", "in", "the", "adenoma–carcinoma", "sequence.", "The", "frequency", "of", "TP53", "mutation", "in", "SAs", "has", "ranged", "from", "5", "to", "50%", "in", "the", "literature.39,41,54", "Although", "a", "link", "between", "MGMT", "loss", "and", "aberrant", "expression", "of", "p53", "is", "supported", "by", "the", "present", "findings,", "it", "should", "be", "noted", "that", "only", "a", "small", "number", "of", "polyps", "showed", "these", "changes", "concurrently." ]

[ 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, 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, 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 ]

[ "Aberrant", "expression", "of", "p53", "and", "correlation", "with", "MGMT", "loss" ]

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

[ "Operating", "system(s):", "all" ]

[ 0, 0, 0 ]

[ "The", "APC", "mutation", "in", "patient", "C633", "was", "also", "detected", "by", "RNA-based", "PTT,", "followed", "by", "cDNA", "sequencing", "and", "genomic", "sequencing", "of", "APC", "exon", "7", "(Figure", "4).", "The", "c.834G", ">", "C", "mutation", "changes", "the", "normal", "splice", "donor", "site", "of", "exon", "7.", "This", "substitution", "reduces", "the", "score", "for", "usage", "of", "the", "wild-type", "splice", "donor", "site", "according", "to", "[37].", "An", "alternative", "cryptic", "splice", "donor", "site", "11", "bp", "upstream", "in", "exon", "7", "is", "used", "in", "the", "mutant", "allele,", "leading", "to", "the", "aberrant", "splicing", "of", "exon", "7.", "The", "resulting", "APC", "mRNA", "carries", "a", "frameshift,", "caused", "by", "the", "11-bp", "deletion", "in", "the", "3'", "end", "of", "exon", "7,", "which", "leads", "to", "the", "premature", "truncation", "of", "the", "protein", "in", "exon", "8.", "A", "third", "novel", "mutation", "affecting", "splicing", "frameshift,", "caused", "by", "the", "11-bp", "deletion", "in", "the", "3'", "end", "of", "exon", "7,", "which", "leads", "to", "the", "premature", "truncation", "of", "the", "protein", "in", "exon", "8", "APC", "aberrant", "splicing", "of", "exon", "7", ".", "The", "resulting", "APC", "mRNA", "carries", "a", "frameshift,", "caused", "by", "the", "11-bp", "deletion", "in", "the", "3'", "end", "of", "exon", "7,", "which", "leads", "to", "the", "premature", "truncation", "of", "the", "protein", "in", "exon", "8.", "A", "third", "novel", "mutation", "affecting", "splicing", "of", "the", "APC", "c.834G", ">", "C", "C633", "mutation", "c.835-7T", ">", "G", "C496", "new", "AG", "splice-acceptor", "site", "eight", "bases", "upstream", "of", "exon", "8", "c.835-7T", ">", "G", " ", "mutation", "(Figure", "3A).", "The", "base", "substitution", "introduces", "a", "new", "AG", "splice-acceptor", "site", "eight", "bases", "upstream", "of", "exon", "8.", "Owing", "to", "the", "use", "of", "this", "new", "splice", "site", "the", "last", "six", "bases", "of", "intron", "7", "are", "included", "in", "the", "transcript,", "resulting", "in", "premature", "truncation", "(Figure", "3B).", "The", "entire", "APC", "coding", "region", "of", "the", "patient", "was", "sequenced", "and", "no", "other", "pathogenic", "variants", "were", "detected.", "A", "search", "for", "deletion", "or", "duplication", "of", "one", "or", "more", "exon", "in", "the", "APC", "gene", "by", "MLPA", "was", "also", "carried", "out", "with", "negative", "result." ]

[ 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, 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, 5, 6, 6, 5, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 6, 21, 5, 6, 6, 6, 6, 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, 21, 5, 6, 6, 9, 5, 5, 6, 6, 9, 5, 6, 6, 6, 6, 6, 6, 6, 6, 6, 5, 6, 6, 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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "Colorectal", "polyps", "have", "traditionally", "been", "classified", "into", "distinct", "histogenetic", "types", "that", "may", "progress", "to", "CRC", "through", "independent", "pathways", "of", "colorectal", "tumorigenesis", "(Table", "2).", "However,", "in", "addition", "to", "the", "two", "‘classical’", "pathways", "to", "CRC", "shown", "in", "Table", "2,", "there", "may", "be", "‘fusion’", "pathways", "that", "combine", "mechanisms", "associated", "with", "both", "adenomas", "and", "serrated", "polyps.", "This", "would", "explain", "why", "many", "CRCs", "display", "phenotypes", "associated", "with", "serrated", "polyps", "as", "well", "as", "adenomas.44", "Three", "possible", "examples", "of", "such", "fusion", "pathways", "are", "shown", "in", "Table", "3.", "It", "is", "difficult", "to", "observe", "directly", "the", "actual", "point", "of", "transition", "from", "benign", "to", "malignant", "colorectal", "lesions.", "Once", "the", "key", "rate-limiting", "step", "is", "achieved", "it", "is", "likely", "that", "the", "transition", "to", "cancer", "occurs", "rapidly", "and", "the", "precursor", "lesion", "is", "then", "overtaken", "by", "the", "malignancy.", "Changes", "leading", "to", "inactivation", "of", "either", "TP535", "or", "the", "DNA", "mismatch", "repair", "gene", "MLH113", "are", "likely", "to", "be", "two", "such", "rate-limiting", "mechanisms.", "Only", "a", "single", "instance", "of", "loss", "of", "expression", "of", "MLH1", "was", "observed", "in", "the", "present", "series", "of", "polyps", "and", "the", "adenoma", "in", "question", "was", "inferred", "to", "be", "from", "a", "patient", "with", "Lynch", "syndrome.24" ]

[ 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, 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, 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 ]

[ "*Statistical", "analysis", "was", "made", "between", "MSI", "and", "MSS", "group", "only" ]

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

[ "KRAS", "mutation", "occurred", "in", "26.5%", "and", "BRAF", "mutation", "in", "4.8%", "of", "adenomas", "(all", "types)", "(Table", "1)", "(P", "<", "0.0001).", "TVAs/VAs", "were", "more", "likely", "to", "have", "KRAS", "mutation", "(50%)", "than", "TAs", "<", " ", "10", "mm", "(18%)", "(P", "<", "0.004)", "or", "TAS", ">", " ", "10", "mm", "in", "diameter", "(17%)", "(P", "<", "0.02).", "In", "the", "case", "of", "TAs", "there", "was", "a", "trend", "for", "KRAS", "mutation", "to", "occur", "more", "frequently", "in", "polyps", "from", "the", "proximal", "colon", "(P", "=", "0.08)", "and", "in", "females", "(P", "=", "0.07)." ]

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

[ "MGMT", "inactivation", "predisposes", "to", "G:T", "mismatches", "and", "chromosomal", "instability", "through", "futile", "cycles", "of", "excision", "and", "repair", "as", "well", "as", "to", "mutation", "of", "KRAS", "and", "TP53.9", "Partial", "methylation", "of", "MLH1", "may", "also", "lead", "to", "low-level", "microsatellite", "instability.37" ]

[ 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 ]

[ "In", "contrast,", "mutations", "accumulate", "throughout", "life", "in", "multistage", "models.", "Genetically", "engineered", "mice", "and", "familial", "cancer", "syndromes", "reveal", "that", "many", "oncogenic", "mutations", "are", "also", "compatible", "with", "normal", "phenotypes", "[11],", "allowing", "for", "the", "possibility", "that", "many", "\"cancer\"", "mutations", "may", "first", "accumulate", "in", "normal-appearing", "colon", "very", "early", "in", "life.", "Such", "pretumor", "progression", "[11]", "more", "readily", "allows", "for", "an", "invasive", "or", "metastatic", "cancer", "phenotype", "at", "transformation", "because", "genetic", "progression", "is", "uncoupled", "from", "tumor", "progression", "(Figure", "2).", "Rather", "than", "incremental", "stepwise", "changes", "in", "phenotype", "after", "each", "new", "mutation,", "a", "tumor", "phenotype", "may", "only", "emerge", "after", "several", "initially", "occult", "mutations", "accumulate", "in", "a", "single", "normal", "appearing", "cell.", "In", "this", "way", "our", "multistage", "model", "can", "apply", "to", "both", "MSI+", "and", "MSI-", "cancers", "despite", "their", "marked", "differences", "in", "types", "of", "mutations", "because", "early", "critical", "mutations", "(whatever", "they", "are)", "do", "not", "visibly", "change", "phenotype", "but", "instead", "accumulate", "in", "normal", "appearing", "colon.", "Early", "or", "advanced", "sporadic", "MSI-", "colorectal", "cancers", "colorectal", "cancers", " ", "[26-28]." ]

[ 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, 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, 0, 0, 0, 0, 0, 0, 0, 1, 2, 1, 2, 0, 0 ]

[ "Although", "the", "positive", "association", "with", "MSI+", "and", "inverse", "association", "with", "KRAS", "hereditary", "non-polyposis", "colorectal", "cancer", " ", "(HNPCC)", "patients", "[5,8-10],", "thus", "providing", "a", "convenient", "discriminator", "between", "sporadic", "and", "familial", "cases.", "The", "majority", "of", "MSI+", "sporadic", "tumors", "belong", "to", "a", "larger", "CRC", "group", "referred", "to", "as", "the", "CpG", "island", "methylator", "phenotype", "(CIMP+)", "that", "is", "characterised", "by", "widespread", "hypermethylation", "of", "CpG", "islands", "located", "with", "gene", "promoter", "regions", "[11].", "Both", "MSI+", "and", "CIMP+", "tumors", "are", "thought", "to", "arise", "from", "large", "hyperplastic", "polyps", "and", "serrated", "adenomas", "[12,13]", "and", "recent", "work", "has", "demonstrated", "a", "high", "frequency", "of", "BRAF", "mutations", "in", "these", "lesions", "[7,14,15]." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 21, 1, 2, 2, 2, 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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "Associations", "between", "BRAF", "mutation", "and", "clinicopathological", "features", "of", "colorectal", "cancer." ]

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

[ "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", "inactivation", "MMR", " ", "inactivation." ]

[ 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, 19, 20, 21, 0, 0 ]

[ "In", "the", "second", "LS", "family,", "the", "index", "subject,", "one", "sister", "and", "one", "brother", "with", "CRC", "(II-5;", "II-6", "II-5", ";", "II-6;", "II-7", ",", "respectively)", "had", "a", "deleterious", "variant", "in", "MSH6", "(c.3013C>T;", "p.Arg1005X)", "but", "did", "not", "have", "the", "p.Lys618Ala", "variant.", "This", "variant", "was", "present", "in", "only", "three", "of", "four", "unaffected", "nephews", "(III-2;", "III-3;", "III-4)", "and", "was", "inherited", "from", "the", "parental", "branch,", "in", "which", "there", "was", "no", "familial", "history", "of", "cancer.", "Individuals", "III-3", "and", "III-4", "inherited", "also", "the", "deleterious", "variant.", "No", "genetic", "testing", "was", "available", "from", "the", "father", "or", "paternal", "relatives", "(", "Family", "#2", ",", "Figure", "3)." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 9, 0, 0, 9, 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, 9, 10, 0, 0, 0 ]

[ "Abstract" ]

[ 0 ]

[ "Mutation", "number", "estimates", "with", "respect", "to", "clinical", "stage", "may", "be", "biased", "with", "the", "Finnish", "data", "because", "it", "includes", "only", "specimens", "with", "tissue", "available", "for", "molecular", "analysis.", "Advanced", "cancers", " ", "may", "not", "be", "removed.", "Therefore,", "a", "similar", "analysis", "was", "performed", "on", "a", "population-based", "cancer", "registry", "[10]", "from", "the", "United", "States", "of", "America", "(SEER", "11", "Regs", "Public-Use,", "Nov", "2001", "Sub", "(1992–1999)),", "which", "records", "ages", "and", "stages", "at", "diagnosis", "regardless", "of", "treatment", "(Table", "2).", "The", "average", "age", "at", "diagnosis", "was", "70.5", "years,", "consistent", "with", "an", "estimate", "of", "six", "mutations", "to", "colorectal", " ", "cancer", "for", "the", "108,275", "white", "males", "and", "females", "average", "age", "at", "diagnosis", "was", "70.5", "years", "9.6%", " ", "of", "all", "cancers)", "or", "HNPCC", "(N", "=", "29", "or", "2.9%", "of", "all", "cancers)", "based", "on", "germline", "MLH1", "or", "MSH2", "mutations", "(Table", "1)." ]

[ 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, 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, 3, 0, 0, 0, 0, 0, 0, 9, 10, 10, 15, 16, 16, 16, 16, 16, 16, 11, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "According", "to", "the", "paradigm", "for", "colorectal", "cancer", "development,", "mutations", "in", "the", "APC", "and", "K-ras", "are", "thought", "to", "contribute", "to", "the", "early", "developmental", "stages", "of", "colorectal", "cancer", "[3].", "However,", "a", "recent", "study", "based", "on", "the", "analysis", "of", "APC,", "K-ras", "and", "TP53", "genes", "concluded", "that", "simultaneous", "occurrence", "of", "all", "three", "genetic", "alterations", "is", "rare", "and", "that", "multiple", "genetic", "pathways", "may", "be", "relevant", "to", "colorectal", "cancer", "[9]." ]

[ 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 ]

[ "Blood", "from", "peripheral", "veins", "(2", "mL)", "was", "taken", "from", "patients", "with", "MSI", "colorectal", "cancer,", "and", "genomic", "DNA", "was", "extracted", "using", "a", "kit", "from", "Beijing", "Bio-Lab", "Materials", "Institute.", "The", "extracted", "genomic", "DNA", "was", "stored", "at", "-80°C", "until", "further", "analysis." ]

[ 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", "frequencies", "of", "BRAF", "mutation", "observed", "in", "MSI-", "(4%)", "and", "MSI+", "(39%)", "tumors", "in", "the", "present", "study", "compare", "favourably", "(", "5%", "tumors", " ", "that", "are", "sporadic", "or", "HNPCC", "in", "origin", "[5,8-10].", "This", "is", "a", "very", "important", "issue", "for", "population-based", "screening", "programs", "that", "aim", "to", "identify", "CRC", "associated", "with", "the", "HNPCC", "syndrome.", "Compared", "to", "the", "analysis", "of", "MLH1", "promoter", "methylation,", "mutation", "at", "the", "BRAF", "V600E", "hotspot", "is", "relatively", "simple", "to", "detect", "using", "DNA", "sequencing,", "RFLP", "or", "the", "SSCP", "method", "used", "in", "the", "present", "work", "(Figure", "1)." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 11, 1, 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 ]

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "Similar", "to", "other", "studies", "[4,5,10,16,17]", "we", "observed", "BRAF", "mutation", "frequencies", "of", "4%", "in", "MSI-", "tumors", "and", "39%", "in", "MSI+", "tumors", "(Table", "1).", "The", "highest", "frequencies", "were", "seen", "in", "tumors", "showing", "methylation", "of", "the", "MLH1", "promoter", "proximal", "region", "(46%)", "and", "in", "tumors", "with", "infiltrating", "lymphocytes", "(48%).", "BRAF", "mutation", "frequencies", "of", "up", "to", "70–80%", "have", "been", "reported", "in", "sporadic", "MSI+,", "CIMP+", "and", "MLH1-methylated", "CRC", "and", "polyps", "[7,8,15,16].", "For", "reasons", "that", "are", "still", "unclear,", "BRAF", "mutations", "are", "approximately", "5–10-fold", "more", "frequent", "in", "tumors", "that", "have", "characteristic", "features", "of", "sporadic", "MSI+", "(ie.", "MLH1", "methylated)", "and", "CIMP+", "phenotypes.", "These", "include", "proximal", "colon", "location,", "poor", "differentiation,", "mucinous", "histology", "and", "infiltrating", "lymphocytes", "[13,19,20].", "Interestingly", "however,", "in", "the", "present", "study", "BRAF", "mutations", "never", "occurred", "in", "association", "with", "KRAS", "mutation,", "were", "present", "in", "only", "3%", "of", "CIMP-", "tumors", "and", "showed", "no", "association", "with", "TP53", "mutation", "(Table", "2).", "The", "observation", "that", "BRAF", "mutations", "occur", "only", "very", "rarely", "in", "HNPCC-related", "MSI+", "CRC", " ", "demonstrates", "that", "defective", "DNA", "mismatch", "repair", "is", "not", "involved", "in", "causing", "this", "genetic", "alteration." ]

[ 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, 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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "Age,", "age", "at", "diagnosis;", "DL,", "duodenal", "lesion;", "dom,", "dominant;", "FGP,", "fundic", "gland", "polyps;", "NA,", "no", "available", "data;", "NI,", "no", "inheritance;", "Number", "of", "polyps,", "number", "of", "polyps", "at", "diagnosis;", "rec,", "recessive" ]

[ 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 ]

[ "Next", "we", "studied", "the", "association", "between", "MMR", "inactivation", "and", "cisplatin", "resistance", "in", "these", "cell", "lines.", "MMR", "inactivation", "seen", "in", "SKOV3", "and", "2774", "might", "result", "in", "the", "relative", "resistance", "to", "cisplatin", "compared", "to", "the", "other", "cell", "lines.", "On", "the", "other", "hand,", "A2780", "cell", "lines", ",", "i.e.", "SKOV6", ",", "HOC7,", "SKOV3,", "2774,", "OVCAR3,", "KB3.1,", "CAOV3", "and", "A2780.", "Microsatellite", "instability", "(MSI),", "which", "is", "a", "marker", "for", "MMR", "inactivation,", "was", "detected", "in", "three", "out", "of", "eight", "cell", "lines", "i.e.", "SKOV3,", "2774", "and", "A2780.", "This", "results", "in", "a", "frequency", "of", "MMR", "inactivation", "in", "ovarian", "cancer", "cell", "lines", "of", "38%.", "The", "MSI", "in", "SKOV3", "can", "be", "explained", "by", "the", "loss", "of", "MLH1", "mRNA", "expression", "which,", "however,", "was", "not", "caused", "by", "promoter", "methylation.", "This", "is", "in", "agreement", "with", "the", "loss", "of", "MLH1", "protein", "expression", "seen", "in", "SKOV3", "described", "in", "a", "study", "of", "the", "60", "NCI", "cancer", "cell", "lines", "[44].", "In", "concordance", "with", "our", "findings,", "2774", "was", "also", "described", "to", "be", "MSI", "[45].", "One", "of", "the", "MSI", "positive", "A2780", "sublines", "showed", "a", "strong", "methylation", "of", "the", "MLH1", "promoter", "without", "MLH1", "mRNA", "expression,", "while", "the", "other", "subline", "showed", "a", "low", "level", "of", "methylation", "and", "relative", "high", "mRNA", "expression.", "Strathdee", "et", "al.", "described", "that", "one", "MLH1", "allele", "was", "methylated", "in", "A2780", "[12]", "which", "is", "comparable", "with", "the", "methylation", "status", "we", "saw", "in", "A2780,", "moreover", "one", "of", "our", "A2780", "sublines", "showed", "complete", "methylation.", "On", "the", "other", "hand,", "another", "study", "did", "not", "detect", "MSI", "in", "A2780", "[11].", "Interestingly,", "Aquilina", "and", "colleagues", "suggested", "there", "is", "a", "subpopulation", "of", "A2780", "cells,", "estimated", "to", "be", "around", "one", "per", "106", "cells", "[46],", "which", "are", "MLH1", "deficient", "and", "heterozygous", "for", "the", "p53phe172", "mutation", "[46,47].", "Since", "these", "cells", "have", "a", "growth", "advantage,", "prolonged", "culturing", "of", "the", "A2780", "cell", "line", "can", "result", "in", "selection", "of", "this", "subpopulation.", "Thus", "over", "time,", "separately", "cultured", "A2780", "can", "have", "varying", "percentages", "of", "cells", "belonging", "to", "this", "subpopulation", "which", "may", "explain", "the", "discrepancies", "in", "MMR", "status", "seen", "in", "the", "A2780", " ", "cell", "lines", "analyzed", "by", "us." ]

[ 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, 9, 9, 10, 0, 0, 9, 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, 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, 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, 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, 9, 0, 0, 0, 0, 0, 0 ]

[ "In", "a", "group", "of", "656", "unselected", "sporadic", "colorectal", "cancer", "patients,", "aberrations", "in", "the", "APC,", "K-ras,", "CTNNB1", "genes,", "and", "expression", "of", "hMLH1", "were", "investigated.", "Additionally,", "tumours", "were", "divided", "in", "groups", "based", "on", "molecular", "features", "and", "compared", "with", "respect", "to", "patient's", "age", "at", "diagnosis,", "sex,", "family", "history", "of", "colorectal", "cancer,", "tumour", "sub-localisation,", "Dukes'", "stage", "and", "differentiation." ]

[ 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", "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", "inactivation.", "In", "contrast,", "Samimi", "et", "al.", "[52]", "found", "an", "inverse", "relation", "between", "MLH1", "protein", "expression", "and", "the", "response", "to", "platinum-based", "chemotherapy", "in", "54", "ovarian", "carcinomas.", "Again,", "the", "number", "of", "ovarian", "carcinomas", "included", "in", "these", "studies", "is", "small", "and", "no", "further", "conclusion", "can", "be", "drawn", "from", "these", "results." ]

[ 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, 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 ]

[ "DNA", "from", "blood", "cells", "(familial", "cancer", "cases", "and", "controls)", "or", "colorectal", "mucosa", "of", "normal", "appearance", "(sporadic", "cases)", "was", "used", "for", "the", "c.1852_1853AA>GC", "sporadic", " ", "and", "familial", "CRC", "cases" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 5, 17, 0, 0, 0, 0, 0 ]

[ "MSI", "was", "detected", "in", "three", "of", "the", "eight", "cell", "lines", "i.e.", "A2780", "(no", "MLH1", "mRNA", "expression", "due", "to", "promoter", "methylation),", "SKOV3", "(no", "MLH1", "mRNA", "expression)", "and", "2774", "(no", "altered", "expression", "of", "MMR", "genes).", "Overall,", "there", "was", "no", "association", "between", "cisplatin", "response", "and", "MMR", "status", "in", "these", "eight", "cell", "lines." ]

[ 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 ]

[ "Data", "were", "prospectively", "collected", "from", "158", "consecutive", "colorectal", "cancer", "patients", " ", "who", "received", "surgical", "treatments", "in", "the", "National", "Colorectal", "Center", "of", "the", "Third", "Affiliated", "Hospital", "of", "Nanjing", "University", "of", "Traditional", "Chinese", "Medicine", "(NUTCM)", "from", "October", "2004", "to", "June", "2006.", "All", "patients", "signed", "an", "informed", "consent", "before", "the", "study.", "Patients", "who", "had", "histologically", "proven", "carcinoma", "and", "received", "operative", "treatment", "in", "our", "hospital", "were", "included", "in", "the", "study.", "Patients", "were", "excluded", "if", "they:", "(1)", "had", "evidence", "of", "concomitant", "ulcerative", "colitis,", "(2)", "presented", "with", "clinically", "unresectable", "diseases,", "(3)", "were", "diagnosed", "with", "FAP", "and", "other", "polyposis", "syndromes,", "(4)", "refused", "operative", "treatment", "or", "refused", "to", "participate", "in", "the", "study.", "This", "study", "was", "approved", "by", "the", "ethical", "committee", "of", "the", "NUTCM." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 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, 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 ]

[ "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)." ]

[ 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 ]

[ "Discussion" ]

[ 0 ]

[ "Mutation", "number", "estimates", "with", "respect", "to", "clinical", "stage", "may", "be", "biased", "with", "the", "Finnish", "data", "because", "it", "includes", "only", "specimens", "with", "tissue", "available", "for", "molecular", "analysis.", "Advanced", "cancers", "may", "not", "be", "removed.", "Therefore,", "a", "similar", "analysis", "was", "performed", "on", "a", "population-based", "cancer", "registry", "[10]", "from", "the", "United", "States", "of", "America", "(SEER", "11", "Regs", "Public-Use,", "Nov", "2001", "Sub", "(1992–1999)),", "which", "records", "ages", "and", "stages", "at", "diagnosis", "regardless", "of", "treatment", "(Table", "2).", "The", "average", "age", "at", "diagnosis", "was", "70.5", "years,", "consistent", "with", "an", "estimate", "of", "six", "mutations", "to", "colorectal", "cancer", "for", "the", "108,275", "white", "males", "and", "females", "with", "stage", "data.", "Like", "the", "Finnish", "cancers", "cancers", ")", "or", "HNPCC", "(N", "=", "29", "cancers", ")", "or", "HNPCC", "(N", "=", "29", "or", "2.9%", "of", "all", "cancers)", "based", "on", "germline", "MLH1", "or", "MSH2", "mutations", "(Table", "1)." ]

[ 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, 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, 0, 0, 0, 0, 0, 11, 9, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "KRAS", "mutation", "occurred", "in", "26.5%", "and", "BRAF", "mutation", "in", "4.8%", "of", "adenomas", "(all", "types)", "(Table", "1)", "(P", "<", "0.0001).", "TVAs/VAs", "were", "more", "likely", "to", "have", "KRAS", "mutation", "(50%)", "than", "TAs", "<", " ", "10", "mm", "(18%)", "(P", "<", "0.004)", "or", "TAS", ">", " ", "10", "mm", "in", "diameter", "(17%)", "(P", "<", "0.02).", "In", "the", "case", "of", "TAs", "there", "was", "a", "trend", "for", "KRAS", "mutation", "to", "occur", "more", "frequently", "in", "polyps", "from", "the", "proximal", "colon", "(P", "=", "0.08)", "and", "in", "females", "(P", "=", "0.07)." ]

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

[ "Frequency", "of", "KRAS", "and", "BRAF", "mutation", "and", "loss", "of", "expression", "of", "O-6-methylguanine", "DNA", "methyltransferase", "(MGMT)", "by", "polyp", "type" ]

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

[ "The", "early", "to", "intermediate", "stages", "of", "the", "majority", "of", "colorectal", "Netherlands", " ", "Cohort", "Study" ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 3, 25, 0, 0, 0 ]

[ "Quantitative", "RT-PCR" ]

[ 0, 0 ]

[ "**", "IGNORE", "LINE", "**" ]

[ 0, 0, 0, 0 ]

[ "The", "mutation", "between", "the", "MSI-L", "and", "MSI-H" ]

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

[ "As", "screening", "method", "for", "HNPCC", "we", "searched", "for", "MSI", "in", "the", "proband's", "primary", "tumor", "and", "metastasis", "tissue", "blocks.", "The", "absence", "of", "proband's", "three", "proband", "relatives", " ", "and", "their", "consent", "for", "release", "of", "medical", "records", "and", "use", "of", "the", "pathological", "tissue", "blocks", "still", "available." ]

[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 9, 11, 9, 10, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]

[ "Results" ]

[ 0 ]

[ "Incident", "cancer", " ", "cases", "are", "identified", "by", "monitoring", "of", "the", "entire", "cohort", "for", "cancer", "occurrence", "through", "annual", "record", "linkage", "to", "the", "Netherlands", "Cancer", "Registry,", "i.e.", "nine", "regional", "cancer", "registries", "throughout", "the", "Netherlands,", "and", "to", "PALGA,", "a", "nationwide", "network", "and", "registry", "of", "histo-", "and", "cytopathology", "[30].", "Together,", "the", "NCR", "and", "PALGA", "provide", "a", "near", "100%", "coverage", "of", "the", "municipalities", "included", "in", "the", "NLCS.", "The", "first", "2.3", "years", "of", "follow", "up", "were", "excluded", "because", "of", "possible", "pre-clinical", "disease", "affecting", "exposure", "status", "and", "because", "of", "incomplete", "nationwide", "coverage", "of", "PALGA", "in", "some", "of", "the", "municipalities", "included", "in", "the", "NLCS", "in", "that", "period.", "From", "1989", "until", "1994,", "929", "incident", "cases", "with", "histologically", "confirmed", "colorectal", "cancer", "were", "identified", "within", "the", "cohort,", "of", "whom", "819", "could", "also", "be", "linked", "to", "a", "PALGA", "report", "of", "the", "lesion." ]

[ 0, 1, 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, 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 ]

[ "No", "MMR", "inactivation", "MSH6", "ovarian", "cancer" ]

[ 7, 8, 8, 21, 1, 2 ]

[ "Families", "carrying", "the", "p.Lys618Ala", "variant" ]

[ 0, 0, 0, 0, 0 ]

[ "Individual", "chromosomal", "islands", "with", "gain", "of", "expression" ]

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

[ "Frequency", "of", "KRAS", "and", "BRAF", "mutation", "and", "loss", "of", "expression", "of", "O-6-methylguanine", "DNA", "methyltransferase", "(MGMT)", "by", "polyp", "type" ]

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

[ "In", "tumors", "tumor", " ", "stages", "or", "on", "the", "identification", "of", "new", "tumor", "subclasses", "and", "their", "diagnostic", "gene", "expression", "signatures", "[1-6].", "In", "contrast,", "much", "less", "is", "known", "about", "the", "influence", "of", "chromosomal", "neighborhood", "on", "gene", "expression", "in", "tumors." ]

[ 0, 1, 1, 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 ]

[ "Thirty-four", "out", "of", "the", "146", "colorectal", "cancers", "(CRCs,", "23.2%)", "were", "MSI,", "including", "19", "MSI-H", "CRCs", "and", "15", "MSI-L", "CRCS.", "Negative", "staining", "for", "MSH2", "was", "found", "in", "8", "CRCs,", "negative", "staining", "for", "MSH6", "was", "found", "in", "6", "CRCs.", "One", "MSI-H", "CRC", "was", "negative", "for", "both", "MSH6", "and", "MSH2.", "Seventeen", "CRCs", "stained", "negatively", "for", "MLH1.", "MLH1", "promoter", "methylation", "was", "determined", "in", "34", "MSI", "CRCs.", "Hypermethylation", "of", "the", "MLH1", "promoter", "occurred", "in", "14", "(73.7%)", "out", "of", "19", "MSI-H", "CRCs", "and", "5", "(33.3%)", "out", "of", "15", "MSI-L", "CRCs.", "Among", "the", "34", "MSI", "carriers", "and", "one", "MSS", "CRC", "with", "MLH1", "negative", "staining,", "8", "had", "a", "MMR", "gene", "germline", "mutation,", "which", "accounted", "for", "23.5%", "of", "all", "MSI", "colorectal", "cancers", "and", "5.5%", "of", "all", "the", "colorectal", "cancers", "MSH6", " ", "and", "MLH1", "on", "tissue", "microarrays", "(TMAs)", "was", "performed,", "and", "methylation", "of", "the", "MLH1", "promoter", "was", "analyzed", "by", "quantitative", "methylation", "specific", "PCR", "(MSP).", "Germline", "mutation", "analysis", "of", "blood", "samples", "was", "performed", "for", "MSH2", ",", "MSH6", " ", "and", "MLH1", "genes." ]

[ 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, 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, 1, 2, 21, 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, 21, 0, 21, 0, 0, 0, 0 ]

[ "Statistical", "analysis" ]

[ 0, 0 ]

[ "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)." ]

[ 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 ]

[ "Note:", "no", "result", "for", "KRAS", "in", "one", "sessile", "serrated", "adenoma", "(SSA)", "and", "one", "tubular", "adenoma", "(TA)", "or", "for", "BRAF", "in", "one", "TA.", "MGMT", "immunstaining", "not", "performed", "in", "15", "polyps", "(seven", "HPs,", "one", "SSA,", "one", "MP", "and", "six", "TAs)." ]

[ 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 ]

[ "Age,", "age", "at", "diagnosis;", "DL,", "duodenal", "lesion;", "dom,", "dominant;", "FGP,", "fundic", "gland", "polyps;", "NA,", "no", "available", "data;", "NI,", "no", "inheritance;", "Number", "of", "polyps,", "number", "of", "polyps", "at", "diagnosis;", "rec,", "recessive" ]

[ 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 ]

[ "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)." ]

[ 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 ]

[ "In", "the", "second", "LS", "family,", "the", "index", "subject,", "one", "sister", "and", "one", "brother", "with", "CRC", "(II-5;", "II-6;", "II-7,", "respectively)", "had", "a", "deleterious", "variant", "in", "MSH6", "(c.3013C>T;", "p.Arg1005X)", "but", "did", "not", "have", "the", "p.Lys618Ala", "variant.", "This", "variant", "was", "present", "in", "only", "three", "of", "four", "unaffected", "nephews", "(III-2;", "III-3;", "III-4)", "and", "was", "inherited", "from", "the", "parental", "branch,", "in", "which", "there", "was", "no", "familial", "history", "of", "cancer.", "Individuals", "III-3", "and", "III-4", "inherited", "also", "the", "deleterious", "variant.", "No", "genetic", "testing", "was", "available", "from", "the", "father", "or", "paternal", "relatives", "(Family", "#2,", "Figure", "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, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]