Original Paper

Cancer Causes & Control

, Volume 17, Issue 5, pp 721-731

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)

  • Gregory J. TranahAffiliated withDepartment of Epidemiology, Harvard School of Public HealthThe Program in Molecular and Genetic Epidemiology, Harvard School of Public HealthCalifornia Pacific Medical Center Research Institute, San Francisco Coordinating Center, UCSF Email author 
  • , James BugniAffiliated withCenter for Environmental Health Sciences, Massachusetts Institute of Technology
  • , Edward GiovannucciAffiliated withDepartment of Epidemiology, Harvard School of Public HealthDepartment of Nutrition, Harvard School of Public HealthChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
  • , Jing MaAffiliated withChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
  • , Charles FuchsAffiliated withChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
  • , Lisa HinesAffiliated withDepartment of Pharmacology, University of Colorado Health Sciences Center
  • , Leona SamsonAffiliated withCenter for Environmental Health Sciences, Massachusetts Institute of Technology
  • , David J. HunterAffiliated withDepartment of Epidemiology, Harvard School of Public HealthThe Program in Molecular and Genetic Epidemiology, Harvard School of Public HealthChanning Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School

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Abstract

Objective

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Colorectal cancer O 6-Methylguanine-DNA methyltransferase Genetic polymorphism Estrogen receptor