Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors

P. T. Campbell, K. Curtin, C. M. Ulrich, W. S. Samowitz, J. Bigler, C. M. Velicer, B. Caan, J. D. Potter, M. L. Slattery

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Background: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. Methods: A study was conducted to examine whether MLH1 (-93G>A and He219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol. Western diet, alcohol and obesity, to investigate potential heterogeneity. Results: The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glut Glu vs Gly/Gly, OR 1.27; 95% Cl 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk IAA vs GG, OR 2.47; 95% Cl 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 He219Val and Western diet (p value interaction: 0.03). Conclusions: The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.

Original languageEnglish (US)
Pages (from-to)661-667
Number of pages7
JournalGut
Volume58
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

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