Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk.
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.
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
Tranah
Gregory J
GJ
Hankinson
Susan E
SE
Samson
Leona D
LD
Hunter
David J
DJ
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011110:Polymorphism, Genetic; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D012307:Risk Factors; D012907:Smoking
D011960:Receptors, Estrogen; D019853:O(6)-Methylguanine-DNA Methyltransferase