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Carcinogenesis Advance Access published online on July 13, 2005
Carcinogenesis, doi:10.1093/carcin/bgi179
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 11, 2005
Revised June 24, 2005
Accepted July 4, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk

Jing Shen 1*, Mary Beth Terry 2, Marilie D. Gammon 3, Mia M. Gaudet 3, Susan L. Teitelbaum 4, Sybil M. Eng 2, Sharon K. Sagiv 3, Alfred I. Neugut 2, and Regina M. Santella 1

1 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032
2 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032
3 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599
4 Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY 10029

* To whom correspondence should be addressed.
Jing Shen, E-mail: js2182{at}columbia.edu.


  Abstract

O6-methylguanine DNA methyl-transferase (MGMT) is the only known critical gene involved in cellular defense against alkylating agents in the DNA direct reversal repair (DRR) pathway. Three single nucleotide polymorphism (SNP) coding for non-conservative amino acid substitutions have been identified [C250T (Leu84Phe), A427G (Ile143Val) and A533G (Lys178Arg)]. To examine the importance of the DRR pathway in risk for breast cancer and the potential interaction with cigarette smoking and dietary antioxidants, we genotyped for these variants using biospecimens from the Long Island Breast Cancer Study Project (LIBCSP). Genotyping was performed by a high throughput assay with fluorescence polarization and included 1,067 cases and 1,110 controls. Overall, there was no main effect between any variant genotype, haplotype or diplotype and breast cancer risk. Heavy smoking (>31 pack-year) significantly increased breast cancer risk for women with the codon 84 variant T-allele (OR =3.0, 95% CI = 1.4-6.2). An inverse association between fruits and vegetables consumption and breast cancer risk was observed among women with the wild-type genotype for codon 84 (OR = 0.8, 95% CI = 0.6-0.9 for ≥ 35 servings of fruits and vegetables per week and CC genotype versus those with < 35 servings per week and CC genotype). The association between fruits and vegetables consumption and reduced breast cancer risk was apparent among women with at least one variant allele for codon 143 (OR = 0.6, 95% CI = 0.5-0.9 for ≥ 35 servings of fruits and vegetables per week and AG or GG genotype versus those with < 35 servings per week and AA genotype). Similar patterns were observed for dietary {alpha}-carotene and supplemental {beta}-carotene, but not for supplemental vitamins C and E. These data suggest that polymorphisms in MGMT may modulate the inverse association previously observed between fruits and vegetables consumption, dietary antioxidants and breast cancer risk and support the importance of fruits and vegetables on breast cancer risk reduction.

Keywords: MGMT; cigarette smoking; dietary antioxidants; breast cancer.
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