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Mismatch repair polymorphisms and risk of colon cancer, tumor microsatellite instability, and interactions with lifestyle factors.
  1. Peter T Campbell (ptcampbe{at}fhcrc.org)
  1. Fred Hutchinson Cancer Research Center, United States
    1. Karen Curtin
    1. University of Utah, United States
      1. Cornelia Ulrich (nulrich{at}fhcrc.org)
      1. Fred Hutchinson Cancer Research Center, United States
        1. Wade Samowitz
        1. University of Utah, United States
          1. Jeanetter Bigler
          1. Fred Hutchinson Cancer Research Center, United States
            1. Christine Velicer
            1. Fred Hutchinson Cancer Research Center, United States
              1. Bette Caan
              1. Kaiser Permanente Med Care Program, United States
                1. John Potter
                1. Fred Hutchinson Cancer Research Center, United States
                  1. Martha Slattery
                  1. University of Utah, United States

                    Abstract

                    Background: Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon and extra-colonic 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: We examined whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1,609 colon cancer cases and 1,972 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 Glu/Glu vs Gly/Gly odds ratio (OR): 1.27; 95% confidence interval (CI): 1.04-1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93 A allele was associated with a more than doubling in MSI-positive colon cancer risk (AA vs GG OR: 2.47; 95%CI: 1.48-4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93 G>A and smoking (MSI-negative colon cancer only, p-value interaction: 0.005); and MLH1 Ile219Val 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.

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