Datasets:

Brizape

/

Variome_split_0404_dev

like 0

[ "Methods" ]

[ 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)." ]

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[ "All", "464", "samples", "without", "a", "truncating", "APC", "mutation", "(n", "=", "411)", "and", "all", "samples", "with", "absent", "hMLH1", "expression", "(n", "=", "58)", "were", "analysed", "for", "mutations", "in", "the", "phosphorylation", "sites", "at", "codons", "33,", "37,", "41", "and", "45", "in", "exon", "3", "of", "the", "CTNNB1", "gene.", "This", "selection", "was", "made,", "since", "most", "mutations", "are", "expected", "in", "these", "samples.", "Tumours", "lacking", "truncating", "APC", "mutations", "may", "harbour", "CTNNB1", "mutations", "[7],", "and", "microsatellite", "instable", "tumours", "are", "also", "expected", "to", "more", "frequently", "have", "mutations", "in", "CTNNB1", "[26]." ]

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[ "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", "which", "has", "clearly", "an", "inactive", "MMR,", "was", "most", "sensitive", "to", "cisplatin.", "Overall,", "there", "seems", "to", "be", "no", "association", "between", "the", "response", "to", "cisplatin", "and", "MMR", "status", "in", "these", "eight", "cell", "lines.", "This", "is", "similar", "to", "a", "study", "in", "the", "60", "NCI", "cell", "lines", "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." ]

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[ "Adenomas" ]

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[ "The", "61", "different", "APC", "mutations", "listed", "in", "Additional", "file", "2", "were", "identified", "among", "81", "of", "the", "96", "families", "of", "the", "Swedish", "Polyposis", "Registry", "that", "were", "screened", "for", "APC", "mutations.", "Fifteen", "of", "the", "cases", "shown", "to", "be", "APC-mutation", "negative", "where", "all", "subjected", "to", "mutational", "screening", "of", "the", "MUTYH", "gene", "and", "six", "of", "them", "were", "shown", "to", "carry", "biallelic", "MUTYH", "mutations", "(reported", "in", "Kanter", "Smoler", "et", "al[31]).", "The", "overall", "mutation-detection", "rate", "in", "APC", "and", "MUTYH", "among", "the", "families", "families", "Family", "1", " ", "is", "the", "largest", "kindred", "in", "the", "Swedish", "Polyposis", "Registry;", "this", "family", "includes", "150", "individuals", "of", "whom", "57", "are", "affected", "by", "the", "disease", "(Figure", "6", "shows", "part", "of", "the", "pedigree).", "However,", "no", "pathogenic", "mutation", "had", "been", "detected", "after", "screening", "the", "whole", "coding", "region", "of", "the", "APC", "gene", "but", "as", "the", "family", "did", "show", "positive", "linkage", "to", "the", "APC", "locus", "we", "decided", "to", "perform", "expression", "analyses", "and", "evidence", "of", "lowered", "APC", "expression", "was", "obtained", "by", "quantitative", "real-time", "PCR", "(Figure", "5A).", "The", "result", "was", "supported", "by", "the", "indication", "of", "a", "lower", "expression", "from", "the", "T-allele", "from", "analysis", "of", "the", "APC", "c.5465A", ">", "T", "polymorphism", "in", "the", "cDNA", "sequencing", "diagram", "of", "two", "affected", "family", "members", "(Figure", "5B).", "The", "search", "for", "mutations", "in", "the", "DNA", "sequence", "of", "the", "APC", "promoters", "has", "been", "initiated,", "but", "no", "pathogenic", "change", "has", "been", "detected", "to", "this", "date.", "The", "possibility", "of", "the", "pathogenic", "change", "being", "epigenetic", "will", "have", "to", "be", "investigated", "further.", "Hypermethylation", "of", "CpG", "sites", "in", "the", "promoter", "of", "APC", "has", "been", "reported", "as", "a", "means", "of", "gene", "silencing", "in", "colorectal", "tumors", "[46-49].", "To", "the", "best", "of", "the", "authors'", "knowledge", "no", "germ-line", "inactivation", "of", "APC", "caused", "by", "promoter", "hypermethylation", "has", "been", "reported.", "However,", "cases", "of", "pathogenic", "germline", "epimutations", "have", "been", "identified", "in", "the", "MLH1", "gene,", "which", "causes", "hereditary", "non-polyposis", "CRC", "[50,51]." ]

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[ "Methods" ]

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[ "Preprocessing", "of", "expression", "data" ]

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[ "Methods" ]

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[ "DNA,", "RNA", "and", "cDNA", "preparation" ]

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[ "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." ]

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[ "Activation", "of", "the", "Wnt", "pathway", "plays", "a", "central", "role", "in", "the", "aetiology", "of", "most", "colorectal", "cancers", "and", "is", "often", "the", "result", "of", "mutations", "in", "the", "N-terminal", "domain", "of", "the", "APC", "gene,", "that", "lead", "to", "partial", "or", "complete", "loss", "of", "this", "region", "and", "thereby", "to", "loss", "of", "the", "β-catenin", "regulating", "function", "[5,6].", "Conversely,", "in", "tumours", "lacking", "these", "APC", "mutations", "[7],", "activating", "missense", "mutations", "at", "one", "of", "the", "phosphorylation", "sites", "at", "codons", "31,", "33,", "37", "and", "45", "of", "exon", "3", "of", "the", "CTNNB1", "gene", "(encoding", "the", "β-catenin", "protein)", "can", "render", "it", "stable", "as", "it", "can", "no", "longer", "be", "tagged", "for", "cellular", "degradation.", "Activation", "of", "the", "Ras", "pathway", "in", "cancer", "is", "marked", "by", "the", "loss", "of", "the", "intrinsic", "GTPase", "activity", "of", "the", "Ras", "protein,", "which", "can", "be", "ascribed", "to", "missense", "mutations", "in", "codons", "12", "and", "13", "of", "exon", "1,", "which", "are", "responsible", "for", "90%", "activating", "mutations", "in", "the", "of", "the", "K-ras", "gene", "[8]." ]

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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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[ "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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