Cancer Causes & Control

, Volume 22, Issue 2, pp 301–309 | Cite as

MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers

  • Kaori Shima
  • Teppei Morikawa
  • Yoshifumi Baba
  • Katsuhiko Nosho
  • Maiko Suzuki
  • Mai Yamauchi
  • Marika Hayashi
  • Edward Giovannucci
  • Charles S. Fuchs
  • Shuji Ogino
Original paper

Abstract

Objective

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme. MGMT promoter hypermethylation and epigenetic silencing often occur as early events in carcinogenesis. However, prognostic significance of MGMT alterations in colorectal cancer remains uncertain.

Methods

Utilizing a database of 855 colon and rectal cancers in two prospective cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study), we detected MGMT promoter hypermethylation in 325 tumors (38%) by MethyLight and loss of MGMT expression in 37% (247/672) of tumors by immunohistochemistry. We assessed the CpG island methylator phenotype (CIMP) using eight methylation markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and LINE-1 (L1) hypomethylation, TP53 (p53), and microsatellite instability (MSI).

Results

MGMT hypermethylation was not associated with colorectal cancer–specific mortality in univariate or multivariate Cox regression analysis [adjusted hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.79–1.36] that adjusted for clinical and tumor features, including CIMP, MSI, and BRAF mutation. Similarly, MGMT loss was not associated with patient survival. MGMT loss was associated with G>A mutations in KRAS (p = 0.019) and PIK3CA (p = 0.0031).

Conclusions

Despite a well-established role of MGMT aberrations in carcinogenesis, neither MGMT promoter methylation nor MGMT loss serves as a prognostic biomarker in colorectal cancer.

Keywords

Colon cancer MGMT Hypermethylation Epigenetics Clinical outcome 

Abbreviations

BMI

Body mass index

CI

Confidence interval

CIMP

CpG island methylator phenotype

HR

Hazard ratio

MGMT

O6-methylguanine-DNA methyltransferase

MSI

Microsatellite instability

MSS

Microsatellite stable

OR

Odds ratio

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Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Kaori Shima
    • 1
  • Teppei Morikawa
    • 1
  • Yoshifumi Baba
    • 1
  • Katsuhiko Nosho
    • 1
  • Maiko Suzuki
    • 1
  • Mai Yamauchi
    • 1
  • Marika Hayashi
    • 1
  • Edward Giovannucci
    • 2
    • 3
  • Charles S. Fuchs
    • 1
    • 2
  • Shuji Ogino
    • 1
    • 4
    • 5
  1. 1.Department of Medical OncologyDana-Farber Cancer Institute and Harvard Medical SchoolBostonUSA
  2. 2.Channing Laboratory, Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Departments of Epidemiology and NutritionHarvard School of Public HealthBostonUSA
  4. 4.Department of PathologyBrigham and Women’s Hospital, and Harvard Medical SchoolBostonUSA
  5. 5.Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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