MGMT promoter methylation, loss of expression and prognosis in 855 colorectal cancers
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.
KeywordsColon cancer MGMT Hypermethylation Epigenetics Clinical outcome
Body mass index
CpG island methylator phenotype
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.
- 33.Irahara N, Nosho K, Baba Y et al. (2010) Precision of pyrosequencing assay to measure LINE-1 methylation in colon cancer, normal colonic mucosa, and peripheral blood cells. J Mol Diagn 12:177–183Google Scholar
- 45.Candiloro IL, Dobrovic A (2009) Detection of MGMT promoter methylation in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter single nucleotide polymorphism. Cancer Prev Res (Phila Pa) 2:862–867Google Scholar