Datasets:

Brizape

/

Variome_split_0404_dev

like 0

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[ "Pedigree", "for", "Family", "#1", "(CRC:", "Colorectal", "cancer;", "GC:", "Gastric", "cancer;", "DC:", "Duodenal", "cancer)." ]

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[ "Large", "deletions", "of", "the", "APC", "gene" ]

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

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[ "Abstract" ]

[ 0 ]

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[ "Results" ]

[ 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" ]

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[ "8q11.23-q21.13" ]

[ 0 ]

[ "Statistics" ]

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[ "Two", "novel", "germline", "APC", "mutations", "that", "introduce", "different", "cryptic", "splice", "sites", "are", "characterized", "in", "this", "study.", "Both", "mutations", "result", "in", "the", "aberrant", "splicing", "of", "APC", "exons", "7", "and", "8", "and", "prematurely", "truncated", "APC", "protein,", "and", "both", "are", "defined", "as", "pathogenic.", "The", "aberrant", "splicing", "identified", "in", "patient", "C496", "(", "c.835-7T", ">", "G", "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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[ "DNA", "isolation" ]

[ 0, 0 ]

[ "We", "genotyped", "the", "p.Lys618Ala", "variant", "in", "MLH1", "in", "1034", "individuals", "(373", "sporadic", "CRC", "patients,", "250", "index", "subjects", "from", "families", "suspected", "of", "having", "LS", "[revised", "Bethesda", "Guidelines]", "and", "411", "controls).", "The", "controls", "were", "selected", "from", "the", "same", "hospitals,", "had", "no", "personal", "histories", "of", "cancer", "and", "had", "diagnoses", "unrelated", "to", "the", "variables", "of", "interest.", "They", "were", "matched", "for", "age,", "gender", "and", "race/ethnicity", "with", "the", "sporadic", "CRC", "patients." ]

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[ "A", "case", "of", "APC", "mosaicism" ]

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[ "The", "K-ras", "mutation", "frequency", "of", "37%", "is", "in", "accordance", "with", "reported", "frequencies", "of", "30", "to", "60%", "[33-43].", "The", "frequency", "of", "37%", "of", "truncating", "mutations", "in", "the", "mutation", "cluster", "region", "of", "APC", "in", "this", "study,", "however,", "seems", "low", "in", "comparison", "to", "the", "general", "assumption", "that", "most", "colorectal", "tumours", "harbour", "a", "mutation", "in", "the", "APC", "gene.", "When", "only", "reports", "from", "studies", "on", "sporadic", "rather", "than", "familial", "colorectal", "cancer", "or", "colorectal", "cancer", "cell", "lines", "are", "considered,", "the", "mutation", "frequencies", "are", "lower", "and", "vary", "between", "30", "and", "70%", "[17,44-49],", "and", "a", "population-based", "case-control", "study", "in", "the", "Netherlands", "reported", "a", "32%", "mutation", "frequency", "[50]." ]

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[ "Since", "ovarian", "cancer", "is", "a", "heterogeneous", "disease", "characterized", "by", "various", "histological", "types", "which", "may", "have", "different", "MSI", "frequencies,", "the", "number", "of", "specimens", "analyzed", "is", "very", "important", "in", "characterizing", "a", "feature", "that", "may", "be", "uncommon", "such", "as", "MSI.", "We", "therefore,", "made", "a", "summary", "of", "20", "studies", "totaling", "1315", "ovarian", "carcinomas,", "to", "compare", "the", "findings", "of", "these", "studies", "with", "our", "results", "(Table", "2).", "The", "MSI", "frequencies", "determined", "in", "these", "studies", "ranged", "from", "0%", "to", "39%.", "Overall,", "MSI", "was", "detected", "in", "165", "of", "the", "1315", "ovarian", "carcinomas", "tested,", "suggesting", "an", "overall", "incidence", "of", "13%", "tumors", "MLH1", "promoter", "methylation", "MLH1", "promoter", "methylation", "carcinomas", "carcinomas", "carcinomas", "carcinomas", " ", "to", "determine", "the", "frequency", "of", "MMR", "inactivation", "in", "ovarian", "cancer", "in", "vivo.", "Seven", "of", "the", "75", "ovarian", "carcinomas", "showed", "MLH1", "promoter", "methylation.", "We", "confirmed", "whether", "the", "observed", "MLH1", "promoter", "methylation", "results", "in", "the", "inactivation", "of", "the", "gene", "by", "determining", "the", "MLH1", "mRNA", "expression", "with", "quantitative", "RT-PCR.", "The", "six", "tumors", "with", "low", "level", "MLH1", "promoter", "methylation", "appeared", "to", "express", "MLH1", "at", "mRNA", "levels", "similar", "to", "that", "of", "the", "unmethylated", "tumors.", "Thus", "a", "low", "level", "of", "methylation", "does", "not", "result", "in", "an", "altered", "expression", "of", "the", "MLH1", "gene.", "In", "contrast,", "the", "abundant", "methylation", "seen", "in", "the", "remaining", "carcinoma", "was", "associated", "with", "the", "lowest", "MLH1", "mRNA", "expression", "level", "of", "all", "50", "ovarian", "carcinomas", "tested.", "However,", "none", "of", "the", "ovarian", "carcinomas", "showed", "MSI", "for", "BAT25,", "BAT26", "and", "for", "BAT40", "or", "D2S123", "which", "suggests", "a", "frequency", "of", "MMR", "inactivation", "of", "0%.", "The", "low", "MLH1", "mRNA", "expression", "seen", "in", "the", "abundant", "methylated", "carcinoma", "might", "be", "sufficient", "enough", "for", "a", "functional", "MMR", "which", "results", "in", "the", "observed", "absence", "of", "MSI." ]

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[ "Of", "656", "tumours", "for", "which", "the", "other", "molecular", "alterations,", "i.e.", "mutations", "in", "the", "APC", "and", "K-ras", "genes", "and", "hMLH1", "expression,", "were", "all", "successfully", "and", "completely", "analysed,", "103", "colorectal", "tumours", "did", "not", "harbour", "a", "truncating", "or", "missense", "APC", "mutation,", "an", "activating", "K-ras", "mutation", "or", "showed", "lack", "of", "hMLH1", "expression,", "as", "depicted", "in", "figure", "1.", "Truncating", "as", "well", "as", "missense", "APC", "mutations", "and", "activating", "K-ras", "mutations", "were", "relatively", "common.", "Truncating", "APC", "mutations", "alone", "and", "activating", "K-ras", "mutations", "in", "codons", "12", "and", "13", "only,", "occurred", "at", "similar", "frequencies", "(20%", "(130/656)", "and", "18%", "(121/656),", "respectively).", "A", "combination", "of", "a", "truncating", "mutation", "in", "APC", "and", "an", "activating", "mutation", "in", "K-ras", "occurred", "less", "often", "than", "the", "sole", "occurrences", "of", "mutations", "in", "both", "genes.", "However,", "as", "shown", "in", "table", "2,", "the", "simultaneous", "occurrence", "of", "mutations", "in", "both", "genes", "occurred", "more", "frequently", "than", "expected", "on", "the", "basis", "of", "chance", "alone.", "A", "χ2", "test", "for", "the", "occurrence", "of", "a", "truncating", "APC", "mutation", "and", "an", "activating", "K-ras", "mutation", "revealed", "that", "the", "occurrence", "of", "these", "mutations", "was", "not", "independent", "(χ2", "=", "8.7,", "P", "<", "0.001),", "but", "the", "correlation", "was", "weak", "(Cramérs", "V", "=", "0.138).", "Finally,", "although", "11", "tumours", "that", "harboured", "a", "mutation", "in", "the", "APC", "or", "K-ras", "gene", "also", "lacked", "hMLH1", "expression,", "hMLH1", "deficiency", "occurred", "more", "frequently", "in", "tumours", "Three", "of", "these", "five", " ", "tumours", "showed", "hMLH1", "deficiency.", "Two", "colorectal", "cancer", "patients", "harboured", "a", "mutation", "in", "the", "CTNNB1", "gene,", "that", "did", "not", "occur", "at", "the", "Ser/Thr", "phosphorylation", "sites,", "but", "would", "result", "in", "an", "amino", "acid", "alteration", "at", "codons", "22", "and", "29,", "the", "effects", "of", "which", "are", "unknown.", "Because", "of", "the", "very", "low", "frequency", "of", "tumours", "harbouring", "a", "CTNNB1", "mutation,", "these", "mutations", "were", "not", "included", "in", "further", "analyses.", "In", "addition,", "mutation", "analysis", "of", "remaining", "samples", "was", "abandoned,", "since", "this", "was", "deemed", "irrelevant", "as", "these", "harboured", "truncating", "APC", "mutations", "and", "are", "considered", "to", "be", "unlikely", "to", "also", "have", "CTNNB1", "mutations", "[7]." ]

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[ "Adenomas" ]

[ 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" ]

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[ "Clinical", "features", "of", "patients", "in", "MSI", "group", "with", "MMR", "gene", "mutations" ]

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[ "P", "=", "0.112" ]

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[ "Tissue", "samples" ]

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[ "Abstract" ]

[ 0 ]

[ "A", "second", "blood", "sample", "was", "obtained", "from", "the", "proband's", "mother", "and", "forwarded", "to", "the", "Department", "of", "Clinical", "Cancer", "Genetics", "(City", "of", "Hope", "Cancer", "Center,", "Duarte,", "California,", "USA)", "to", "full", "mutation", "analysis", "of", "the", "hMSH2", "tumor", "proband's", " ", "primary", "tumor", "(T')", "and", "its", "metastasis", "(T\")", "of", "those", "inherited", "from", "his", "biological", "mother", "(BM)", "and", "father", "(BF)." ]

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[ "Conclusion" ]

[ 0 ]

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

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

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[ "Jass", "J", "R,", "Baker", "K,", "Zlobec", "I,", "Higuchi", "T,", "Barker", "M,", "Buchanan", "D", "&", "Young", "J", "(2006)", "Histopathology", "49,", "121–131" ]

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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", "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", "germline", "epimutations", "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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[ "Statistical", "analysis" ]

[ 0, 0 ]

[ "Abstract" ]

[ 0 ]

[ "Advanced", "colorectal", "polyps", "with", "the", "molecular", "and", "morphological", "features", "of", "serrated", "polyps", "and", "adenomas:", "concept", "of", "a", "‘fusion’", "pathway", "to", "colorectal", "cancer" ]

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[ "Abstract" ]

[ 0 ]

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