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

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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.

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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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Acknowledgments

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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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Kaori Shima, Teppei Morikawa, Yoshifumi Baba, Katsuhiko Nosho, Maiko Suzuki, Mai Yamauchi, Marika Hayashi, Charles S. Fuchs & Shuji Ogino

  2. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Edward Giovannucci & Charles S. Fuchs

  3. Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA

    Edward Giovannucci

  4. Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA

    Shuji Ogino

  5. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, 44 Binney St., Room JF-215C, Boston, MA, 02115, USA

    Shuji Ogino

Authors
  1. Kaori Shima
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  2. Teppei Morikawa
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  3. Yoshifumi Baba
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  4. Katsuhiko Nosho
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  5. Maiko Suzuki
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  6. Mai Yamauchi
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  7. Marika Hayashi
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  8. Edward Giovannucci
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  9. Charles S. Fuchs
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  10. Shuji Ogino
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Corresponding author

Correspondence to Shuji Ogino.

Additional information

Kaori Shima, Teppei Morikawa and Yoshifumi Baba contributed equally.

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Shima, K., Morikawa, T., Baba, Y. et al. MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers. Cancer Causes Control 22, 301–309 (2011). https://doi.org/10.1007/s10552-010-9698-z

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  • DOI: https://doi.org/10.1007/s10552-010-9698-z

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