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Pharmacogenet Genomics. 2006 Jul;16(7):469-74.

Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk.

Author information

1
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

Abstract

OBJECTIVE:

Endogenous and exogenous estrogens influence breast cancer risk by interacting with estrogen receptor (ER). The O-methylguanine DNA methyltransferase (MGMT) gene has a dual role in repairing alkylation damage and in inhibiting ER-mediated cell proliferation. We assessed the two MGMT polymorphisms, Leu84Phe and Ile143Val, with breast cancer risk. We also evaluated the potential interactions between the two polymorphisms and estrogen-related risk factors and cigarette smoking on breast cancer risk.

METHODS:

We conducted a nested case-control study within the Nurses' Health Study (1311 cases, 1760 controls).

RESULTS:

Compared with the 84Leu/Leu genotype, the Phe/Phe genotype had a multivariate odds ratio (OR) of 1.68 (95% confidence interval (CI), 0.98-2.88). This positive association was magnified among postmenopausal women with body mass index>25 (OR, 3.01; 95% CI, 1.30-6.94), those in the highest tertile of pre-diagnostic plasma endogenous estradiol levels (Phe carriers versus non-carriers, OR, 2.42; 95% CI, 1.49-3.94), non-current postmenopausal hormone users (OR, 2.60; 95% CI, 1.19-5.64), and possibly estrogen receptor-positive cases (OR, 1.82; 95% CI, 0.99-3.35). We did not observe a main effect of the Ile143Val polymorphism or its interactions with these factors. No interaction was observed between either of the polymorphisms and cigarette smoking on breast cancer risk.

CONCLUSIONS:

These data suggest that the Leu84Phe polymorphism affect the capacity of MGMT to inhibit estrogen receptor-mediated cell proliferation and is associated with breast cancer risk.

[Indexed for MEDLINE]

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