期刊
CANCER CAUSES & CONTROL
卷 22, 期 2, 页码 301-309出版社
SPRINGER
DOI: 10.1007/s10552-010-9698-z
关键词
Colon cancer; MGMT; Hypermethylation; Epigenetics; Clinical outcome
资金
- U.S. National Institute of Health (NIH) [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, R01 CA151993]
- Bennett Family Fund
- Entertainment Industry Foundation National Colorectal Cancer Research Alliance
- Uehara Memorial Foundation
- Japan Society for Promotion of Science
O (6)-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.
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