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



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.


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).


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).


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.


Colon cancer MGMT Hypermethylation Epigenetics Clinical outcome 



Body mass index


Confidence interval


CpG island methylator phenotype


Hazard ratio


O6-methylguanine-DNA methyltransferase


Microsatellite instability


Microsatellite stable


Odds ratio



We deeply thank the Nurses’ Health Study and Health Professionals Follow-up Study cohort participants who have generously agreed to provide us with biological specimens and information through responses to questionnaires, and hospitals and pathology departments throughout the United States for providing us with medical records and tumor tissue specimens. This work was supported by U.S. National Institute of Health (NIH) grants P01 CA87969 (to SE Hankinson), P01 CA55075 (to WC Willett), P50 CA127003 (to CSF), K07 CA122826 (to SO), and R01 CA151993 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. Y.B. was supported by a fellowship grant from the Uehara Memorial Foundation. K.N. and M.S. were supported by fellowship grants from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

No conflicts of interest exist.


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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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