Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk

Pharmacogenet Genomics. 2006 Jul;16(7):469-74. doi: 10.1097/01.fpc.0000215065.21718.4c.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Middle Aged
  • O(6)-Methylguanine-DNA Methyltransferase / genetics*
  • Polymorphism, Genetic
  • Receptors, Estrogen / antagonists & inhibitors
  • Risk Factors
  • Smoking


  • Receptors, Estrogen
  • O(6)-Methylguanine-DNA Methyltransferase