Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2015
Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors.
Сравнительное исследованиеСтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Levine A Joan, Phipps Amanda I, Baron John A, Buchanan Daniel D, Ahnen Dennis J, Cohen Stacey A, Lindor Noralane M, Newcomb Polly A, Rosty Christophe, Haile Robert W, Laird Peter W, Weisenberger Daniel J
Аннотация
BACKGROUND: The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1.
METHODS: We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables.
RESULTS: Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82).
CONCLUSIONS: These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis.
IMPACT: MLH1 DNA methylation status should be taken into account in etiologic studies.
METHODS: We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables.
RESULTS: Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82).
CONCLUSIONS: These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis.
IMPACT: MLH1 DNA methylation status should be taken into account in etiologic studies.
Предметные рубрики MeSH
Adaptor Proteins, Signal TransducingAgedBiomarkers, TumorCase-Control StudiesColorectal NeoplasmsCpG IslandsDNA MethylationFemaleFollow-Up StudiesGene Expression Regulation, NeoplasticHumansMaleMicrosatellite InstabilityMiddle AgedMutL Protein Homolog 1MutationNeoplasm StagingNuclear ProteinsPrognosisPromoter Regions, GeneticRisk FactorsSurvival Rate