© The Author 2007. Published by Oxford University Press.
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MLH1 –93G>A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer
Affiliations of authors: Departments of Pathology and Laboratory Medicine (SR, MM, VVP, BB) and Surgery (SSG), Samuel Lunenfeld Research Institute (SR, MM, VVP, SSG, JRM, JAK, BB), and Prosserman Centre for Health Research (JRM, JAK), Mount Sinai Hospital, Toronto, ON, Canada; Departments of Laboratory Medicine and Pathobiology (SR, MM, YMC, BB), Surgery (SSG), and Public Health Sciences (JRM, JAK), University of Toronto, Toronto, ON, Canada; Departments of Genetics (RCG, BHY) and Clinical Epidemiology (PSP), and Faculty of Medicine (ED), Memorial University, St John’s, NL, Canada; Ontario Familial Colorectal Cancer Registry, Cancer Care Ontario, Toronto, ON, Canada (NM, DD)
Correspondence to: Bharati Bapat, PhD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray St, L6-304B, Box 30, Toronto, ON, Canada M5T 3L9 (e-mail: bapat{at}mshri.on.ca).
Background: Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer.
Methods: We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay. Tumor microsatellite instability (MSI) was determined with a polymerase chain reaction–based method; MSI status was assigned as high (MSI-H, 
30% unstable markers among all markers tested), low (MSI-L, <30% markers unstable), or stable (MSS, no unstable markers). 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-square or Fisher's exact test. All statistical tests were two-sided.
Results: We observed strong associations between the MLH1 –93G>A polymorphism and MSI-H tumors among case patients from Ontario (P = .001) and Newfoundland (P = .003). When compared with the control populations, homozygosity for the MLH1 –93G>A variant allele was associated with MSI-H tumors among case patients in Ontario (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.65 to 6.30) and in Newfoundland (OR = 8.88, 95% CI = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% CI = 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% CI = 1.14 to 5.75). Genotype frequencies were similar among case patients with MSS and MSI-L tumors and control subjects, and the majority of homozygous variant carriers had MSS tumors. Among case patients from Ontario, an association between the MLH1 –93G>A polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed.
Conclusion: In two patient populations, the MLH1 –93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.
| CONTEXT AND CAVEATS Prior knowledge Approximately 30% of patients with colorectal cancer have a positive family history of this disease, but few colorectal cancers can be explained by mutations in high-penetrance genes. Study design Population-based case–control study in two different populations. Contribution In two populations, a polymorphism in a mismatch repair gene, MLH1, was shown to be associated with an increased risk of colorectal cancer with high microsatellite instability. Implications A common polymorphism in the MLH1 gene may account for an increased risk of colorectal cancer in some patients. Limitations A potential source of bias was self-reported ethnicity. The authors tried to minimize this bias by excluding subjects who did not report ethnicity or reported non-white ethnicity.
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Manuscript received October 30, 2006; revised January 18, 2007; accepted February 2, 2007.
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J Natl Cancer Inst 2007 99: 1490.
J Natl Cancer Inst 2007 99: 413.
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