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Endometrial Cancer Risk Is Associated with Variants of the Mismatch Repair Genes MLH1 and MSH2

¹ Centre for Research in Women's Health and ² Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Toronto; ³ Division of Gynecologic Oncology and ⁴ Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto; ⁵ Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; and ⁶ Lifetime Cancer Screening and Prevention Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida

Requests for reprints: Steven A. Narod, Centre for Research in Women's Health, 790 Bay Street, Toronto, Ontario, Canada M5G 1N8. Phone: 416-351-3765; Fax: 416-351-3767. E-mail: steven.narod{at}sw.ca

Women with germ-line mutations in the mismatch repair genes (responsible for hereditary nonpolyposis colorectal cancer) face an increased risk of colonic and endometrial cancer. However, these germ-line mutations are rare and are responsible for fewer than 1% of endometrial cancers. Therefore, we examined whether or not common variants of the hereditary nonpolyposis colorectal cancer–associated genes might also be associated with an increased risk of endometrial cancer. Three single-nucleotide polymorphisms were selected in the MLH1 and MSH2 mismatch repair genes. All the various 672 women with endometrial cancer and 880 controls were genotyped. Each of these three single-nucleotide polymorphisms was associated with an increased risk of endometrial cancer. Carriers of the MLH1 nt-93 A allele were at a 1.5-fold increased risk of developing endometrial cancer compared with controls [95% confidence interval (95% CI), 1.2-2.0; P = 0.001]. The risk was higher for homozygote carriers [odds ratio (OR), 1.9; 95% CI, 1.2-3.2; P = 0.009]. For carriers of the MSH2 rs2303428 C allele, the OR was 1.4 (95% CI, 1.0-1.9; P = 0.05), and for carriers of the MSH2 rs2059520 G allele, the OR was 1.3 (95% CI, 1.0-1.7; P = 0.03). More than 9% of endometrial cancer cases carried a variant allele in both MLH1 and MSH2. For these women, the risk of endometrial cancer was particularly high (OR, 2.1; 95% CI, 1.2-3.6; P = 0.005). For patients younger than 50 years at diagnosis who carried both variants, the risk was even higher (OR, 3.4; 95% CI, 1.7-6.6; P = 0.0005). In summary, two common variant alleles of the MLH1 and MSH2 genes make a substantial contribution to endometrial cancer incidence in Ontario. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1636–40)

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