TY - JOUR
T1 - Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors
AU - Campbell, P. T.
AU - Curtin, K.
AU - Ulrich, C. M.
AU - Samowitz, W. S.
AU - Bigler, J.
AU - Velicer, C. M.
AU - Caan, B.
AU - Potter, J. D.
AU - Slattery, M. L.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
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U2 - 10.1136/gut.2007.144220
DO - 10.1136/gut.2007.144220
M3 - Article
C2 - 18523027
AN - SCOPUS:66349113849
SN - 0017-5749
VL - 58
SP - 661
EP - 667
JO - Gut
JF - Gut
IS - 5
ER -