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Polymorphisms in O6-methylguanine DNA methyltransferase and breast cancer risk

Jiali Han1, Gregory J Tranah, Susan E Hankinson

  • 1Channing 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

Pharmacogenetics and Genomics
|June 22, 2006
PubMed
Abstract

Insights

The O-methylguanine DNA methyltransferase (MGMT) Leu84Phe polymorphism is linked to increased breast cancer risk, particularly in postmenopausal women with higher BMI or estrogen levels. The Ile143Val variant showed no significant association.

Area of Science:

  • Genetics and Cancer Epidemiology
  • Molecular Biology and Cancer Research

Background:

  • Estrogen receptor (ER) signaling is a key driver of breast cancer, influenced by endogenous and exogenous estrogens.
  • The O-methylguanine DNA methyltransferase (MGMT) gene plays a role in DNA repair and can inhibit ER-mediated cell proliferation.
  • Genetic variations in MGMT may influence breast cancer risk by altering its cellular functions.

Purpose of the Study:

  • To investigate the association between two MGMT gene polymorphisms (Leu84Phe and Ile143Val) and breast cancer risk.
  • To evaluate potential interactions between these MGMT polymorphisms and established breast cancer risk factors, including estrogen levels, hormone use, BMI, and smoking.

Main Methods:

  • A nested case-control study was conducted within the large Nurses' Health Study cohort.
  • Genotyping for MGMT Leu84Phe and Ile143Val polymorphisms was performed on 1311 cases and 1760 controls.
  • Statistical analyses assessed the odds ratios (OR) and 95% confidence intervals (CI) for breast cancer risk associated with each genotype and its interactions with risk factors.

Main Results:

  • The MGMT Leu84Phe polymorphism, specifically the Phe/Phe genotype, was associated with an increased breast cancer risk (OR, 1.68).
  • This association was significantly stronger among postmenopausal women with a body mass index > 25 (OR, 3.01) and those with high endogenous estradiol levels (OR, 2.42).
  • An increased risk was also observed for non-current postmenopausal hormone users (OR, 2.60) and possibly for estrogen receptor-positive cases (OR, 1.82). The Ile143Val polymorphism showed no significant main effect or interactions.

Conclusions:

  • The MGMT Leu84Phe polymorphism appears to influence breast cancer risk, potentially by affecting MGMT's ability to inhibit ER-mediated proliferation.
  • These findings highlight the role of MGMT genetic variations in breast cancer etiology, particularly in interaction with hormonal factors.

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