Cancer Causes & Control

, Volume 17, Issue 5, pp 721–731 | Cite as

O6-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. Tranah
  • James Bugni
  • Edward Giovannucci
  • Jing Ma
  • Charles Fuchs
  • Lisa Hines
  • Leona Samson
  • David J. Hunter
Original Paper

Abstract

Objective

O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6-position of guanine in DNA. Unrepaired O6-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 O6-Methylguanine-DNA methyltransferase Genetic polymorphism Estrogen receptor 

Abbreviations

NHS

Nurses’ Health Study

HPFS

Health Professionals Follow-Up Study

MGMT

O6-methylguanine-DNA methyltransferase

NNN

N′-nitrosonornicotine

NNK

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

NDMA

N-nitrosodimethylamine

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Copyright information

© Springer 2006

Authors and Affiliations

  • Gregory J. Tranah
    • 1
    • 3
    • 7
  • James Bugni
    • 5
  • Edward Giovannucci
    • 1
    • 2
    • 4
  • Jing Ma
    • 4
  • Charles Fuchs
    • 4
  • Lisa Hines
    • 6
  • Leona Samson
    • 5
  • David J. Hunter
    • 1
    • 3
    • 4
  1. 1.Department of EpidemiologyHarvard School of Public HealthBostonUSA
  2. 2.Department of NutritionHarvard School of Public HealthBostonUSA
  3. 3.The Program in Molecular and Genetic EpidemiologyHarvard School of Public HealthBostonUSA
  4. 4.Channing Laboratory, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  5. 5.Center for Environmental Health SciencesMassachusetts Institute of TechnologyCambridgeUSA
  6. 6.Department of PharmacologyUniversity of Colorado Health Sciences CenterDenverUSA
  7. 7.California Pacific Medical Center Research InstituteSan Francisco Coordinating Center, UCSFSan FranciscoUSA

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