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Carcinogenesis Advance Access published online on October 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm229
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MSH2 –118T>C and MSH6 –159C>T Promoter Polymorphisms and the Risk of Colorectal Cancer

Miralem Mrkonjic1,2,3, Stavroula Raptis1,2,3, Roger C. Green4, Neerav Monga5, Darshana Daftary5, Elizabeth Dicks6, H. Banfield Younghusband4, Patrick S. Parfrey7, Steven S. Gallinger2,8,9, John R. McLaughlin2,10,11, Julia A. Knight2,10,11 and Bharati Bapat1,2,3,*

1 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
4 Department of Genetics, Memorial University, St. John's, NL, Canada
5 Ontario Familial Colorectal Cancer Registry, Cancer Care Ontario, Toronto, ON, Canada
6 Faculty of Medicine, Memorial University, St. John's, NL, Canada
7 Department of Clinical Epidemiology, Memorial University, St. John's, NL, Canada
8 Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
9 Department of Surgery, University of Toronto, Toronto, ON, Canada
10 Prosserman Centre for Health Research, Mount Sinai Hospital, Toronto, ON, Canada
11 Department of Public Health Sciences, University of Toronto, Toronto, ON, Canada

* Correspondence to: Bharati Bapat, PhD, Samuel Lunenfeld Research Institute, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 60 Murray Street, L6-304B, Box 30, Toronto, ON, Canada M5T 3L9 (telephone no.: (416) 586-4800 ext. 5175; fax no.: (416) 361-2655; e-mail: bapat{at}mshri.on.ca).

Background and Aims: The most important indicator of colorectal cancer risk is the presence of family history of the disease. Inherited genetic changes, such as single nucleotide polymorphisms, in key candidate genes may contribute to colorectal cancer risk. We investigated whether promoter polymorphisms in DNA mismatch repair genes MSH2 and MSH6 are associated with the risk of colorectal cancer.

Methods: We genotyped 929 colorectal cancer patients and 1098 control subjects from Ontario, and 467 patients and 344 controls from Newfoundland and Labrador, for two promoter polymorphisms in the mismatch repair genes MSH2 and MSH6 using the fluorogenic 5' nuclease assay. We used unconditional logistic regression to evaluate the association between each polymorphism and colorectal cancer after adjusting for age and sex. The associations between polymorphisms and tumor clinicopathologic features were evaluated with a Pearson's chi-squared or Fisher's exact test. All statistical tests were two-sided.

Results: We observed strong associations between the MSH2 -118T>C polymorphism and family history of colorectal cancer, based on the Amsterdam criteria I (P=0.005), and Amsterdam criteria I and II (P=0.036) among cases from Ontario. This association was especially evident among female colorectal cancer patients in Ontario (for Amsterdam criteria I, and I and II combined, P=0.003 and P=0.0001, respectively).

Conclusion: The MSH2 -118T>C polymorphism was associated with strong family history of colorectal cancer in Ontario patients.

Received July 19, 2007; revised August 31, 2007; accepted September 28, 2007.


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