O 6 -Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)
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O 6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O 6-position of guanine in DNA. Unrepaired O 6-methylguanines result in G:C to A:T transitions in mutated K-ras and p53 in colorectal tumors. Two non-synonymous MGMT coding region variants, Leu84Phe and Ile143Val, lie in close proximity to the reactive 145Cys residue and to a conserved estrogen receptor interacting helix.
We assessed the association between the MGMT Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in two nested case–control studies: one each in the Nurses’ Health Study (NHS) and the Physicians’ Health Study (PHS) cohorts.
Among 197 female cases and 2,500 controls from the NHS, the variant 143Val allele was significantly associated with reduced risk of colorectal cancer [odds ratio (OR)=0.52, 95% confidence interval (CI) 0.33–0.80]. In women, statistically significant gene-environment interactions were found between the Leu84Phe polymorphism and alcohol intake (P=0.03), BMI (P=0.04) and postmenopausal hormone use (P=0.03). The Leu84Phe and Ile143Val polymorphisms were not significantly associated with risk of colorectal cancer among 271 male cases and 451 controls from the PHS.
Our results suggest that the common Leu84Phe and Ile143Val polymorphisms in MGMT influence risk of colorectal cancer in women possibly through modulating estrogen receptor-dependent transcriptional activation, which has previously been shown to occur in response to DNA alkylation damage.
- O 6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)
Cancer Causes & Control
Volume 17, Issue 5 , pp 721-731
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers
- Additional Links
- Colorectal cancer
- O 6-Methylguanine-DNA methyltransferase
- Genetic polymorphism
- Estrogen receptor
- Industry Sectors
- Author Affiliations
- 1. Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
- 3. The Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
- 7. California Pacific Medical Center Research Institute, San Francisco Coordinating Center, UCSF, 185 Berry Street, Lobby 4, Suite 5700, San Francisco, CA, 94107-1728, USA
- 5. Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
- 2. Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
- 4. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA, 02115, USA
- 6. Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO, 80262, USA