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. TranahEmail author
  • James Bugni
  • Edward Giovannucci
  • Jing Ma
  • Charles Fuchs
  • Lisa Hines
  • Leona Samson
  • David J. Hunter
Original Paper



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.


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.


Colorectal cancer O6-Methylguanine-DNA methyltransferase Genetic polymorphism Estrogen receptor 



Nurses’ Health Study


Health Professionals Follow-Up Study


O6-methylguanine-DNA methyltransferase









We thank the participants of the Nurses’ Health Study and Physicians’ Health Study for their cooperation and participation. Supported by National Institutes of Health research grants CA70817, CA87969, CA34944, CA-40360, HL-26490 and HL-34595. G.J.T. is supported by training grant CA 09001–27 from the National Institutes of Health.


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Copyright information

© Springer 2006

Authors and Affiliations

  • Gregory J. Tranah
    • 1
    • 3
    • 7
    Email author
  • 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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