Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk.
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.
Han
Jiali
J
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School 181 Longwood Avenue, Boston, MA 02115, USA. jiali.han@channing.harvard.edu
Hankinson
Susan E
SE
De Vivo
Immaculata
I
D000328:Adult; D016022:Case-Control Studies; D049109:Cell Proliferation; D004249:DNA Damage; D016889:Endometrial Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000737:chemistry*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012306:Risk; D012907:Smoking
D019853:O(6)-Methylguanine-DNA Methyltransferase