Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors
- P T Campbell1,
- K Curtin2,
- C M Ulrich1,3,
- W S Samowitz4,
- J Bigler1,
- C M Velicer1,
- B Caan5,
- J D Potter1,3,
- M L Slattery2
- 1Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- 2Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- 3Department of Epidemiology, University of Washington, Seattle, Washington, USA
- 4Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- 5Division of Research, Kaiser Permanente Medical Care Program, Oakland, California, USA
- Dr C Ulrich, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M4-B402, Seattle, WA 98109-1024, USA; nulrich{at}fhcrc.org
- Revised 2 May 2008
- Accepted 14 May 2008
- Published Online First 3 June 2008
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 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.
Footnotes
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Funding: This study was funded by NIH Grants R01 CA48998, R01 CA59045, R01 CA61757 and U54 CA116847. This research was supported by the Utah Cancer Registry, which is funded by Contract #N01-PC-67000 from the National Cancer Institute, with additional support from the State of Utah Department of Health and the University of Utah, the Northern California Cancer Registry and the Sacramento Tumor Registry. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of the National Cancer Institute.
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Competing interests: None.
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Ethics approval: Ethics approval was obtained for this study.
