Carcinogenesis Advance Access originally published online on June 15, 2006
Carcinogenesis 2006 27(11):2281-2285; doi:10.1093/carcin/bgl099
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Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk
1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School 181 Longwood Avenue, Boston, MA 02115, USA
2 Department of Epidemiology 665 Huntington Avenue, Boston, MA 02115, USA
3 The Program in Molecular and Genetic Epidemiology, Harvard School of Public Health 665 Huntington Avenue, Boston, MA 02115, USA
*To whom correspondence should be addressed. Tel: +1 617 525 2098; Email: jiali.han{at}channing.harvard.edu
Cigarette smoking is inversely associated with endometrial cancer risk. Smoking is proposed to decrease risk, in large part, through its anti-estrogenic effects in the uterus. In addition, cigarette smoke is a major source of alkylation damage. The O6-methylguanine DNA methyltransferase (MGMT) gene is responsible for repairing alkylation DNA damage and also has a role in inhibiting estrogen receptor-mediated cell proliferation. Because of MGMT's dual functions, it is a strong candidate gene for endometrial cancer. We assessed the two functional polymorphisms, the Leu84Phe and Ile143Val, in relation to endometrial cancer risk in a nested case–control study within the Nurses’ Health Study (cases = 456, controls = 1134). Compared with the 84Leu/Leu genotype, the Phe carriers had a significantly decreased risk of endometrial cancer [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.53–0.96]. We did not observe an association between the Ile143Val polymorphism and endometrial cancer risk overall. We observed a significant multiplicative interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk (P, interaction, 0.04); the inverse association of pack-years with endometrial cancer risk was limited to the 143Val carriers (P, trend, 0.01). Compared with women who had the Ile/Ile genotype and never smoked, the 143Val carriers who had >30 pack-years of smoking had a significantly decreased risk of endometrial cancer (OR, 0.41; 95%CI, 0.19–0.86). These data suggest that these two polymorphisms may influence endometrial cancer risk.
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