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

• Published in: Gut Vol. 58; no. 5; pp. 661 - 667
• Main Authors: Campbell, P T, Curtin, K, Ulrich, C M, Samowitz, W S, Bigler, J, Velicer, C M, Caan, B, Potter, J D, Slattery, M L
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.05.2009; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Age; Aged; Alcohol; Biological and medical sciences; Body mass index; Colonic Neoplasms - genetics; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Data collection; Deoxyribonucleic acid; Diet; Diet - adverse effects; DNA; DNA Mismatch Repair - genetics; DNA repair; DNA-Binding Proteins - genetics; Epidemiology; Family medical history; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Frequency; Genotype; Germ-Line Mutation - genetics; Health surveillance; Humans; Inflammatory bowel disease; Laboratories; Life Style; Lifestyles; Male; Medical research; Medical sciences; Microsatellite Instability; Middle Aged; Mutation; Mutation, Missense - genetics; MutL Protein Homolog 1; Nuclear Proteins - genetics; Polymorphism, Genetic - genetics; Public health; Risk Assessment; Risk Factors; Smoking; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Tumors; Twins; United States; Colonic disease; Colon cancer; Microsatellite DNA; Risk factor; Gastroenterology; Digestive diseases; Intestinal disease; Instability; Malignant tumor; Cancer; Polymorphism
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2007.144220

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 Ile219Val) 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 Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 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 (AA vs GG, OR 2.47; 95% CI 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 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.