Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk

Jiali Han, Gregory J. Tranah, Susan E. Hankinson, Leona D. Samson, David J. Hunter

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)469-474
Number of pages6
JournalPharmacogenetics and Genomics
Volume16
Issue number7
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

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Methyltransferases
Estrogen Receptors
Odds Ratio
Confidence Intervals
Breast Neoplasms
DNA
Estrogens
Smoking
Genotype
Cell Proliferation
Alkylation
Case-Control Studies
Estradiol
Body Mass Index
Nurses
O-(6)-methylguanine
Hormones
Health
Genes

Keywords

  • Breast cancer
  • Estrogen
  • MGMT

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk. / Han, Jiali; Tranah, Gregory J.; Hankinson, Susan E.; Samson, Leona D.; Hunter, David J.

In: Pharmacogenetics and Genomics, Vol. 16, No. 7, 01.01.2006, p. 469-474.

Research output: Contribution to journalArticle

Han, Jiali ; Tranah, Gregory J. ; Hankinson, Susan E. ; Samson, Leona D. ; Hunter, David J. / Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk. In: Pharmacogenetics and Genomics. 2006 ; Vol. 16, No. 7. pp. 469-474.
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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.",
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AB - 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.

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