Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 42, Issue 1, Pages 127-133Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2012.1682
Keywords
APC1A; colorectal cancer; CpG sites; DNA methylation; O-6-MGMT; p14(ARF); p16(INK4a); preterapeutic predictor; prognosis; Pyrosequencing (R); RASSF1A; survival; tumor stage; tumor differentiation
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Funding
- Orebro County Council, Nyckelfonden, Orebro
- Lions Cancerfond, Uppsala
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We quantitated the methylated fraction of CpG sites in the promoter regions of O-6-MGMT, p14(ARF), p16(INK4a), RASSF1A and APC1A in tumor tissue from patients with colorectal cancer (CRC) in order to determine if promoter hypermethylation of any of these genes predicts survival. DNA was isolated from 111 primary CRC and 46 matched normal colorectal mucosa samples from the same patients, obtained at primary surgery and DNA methylation was examined by Pyrosequencing (R). Follow-up time was up to 20 years. Patients showed partial promoter methylation in the following frequencies: O-6-MGMT, 34%; p14(ARF), 29%; p16(INK4a), 28%; RASSF1A, 14%; and APC1A, 27%. Normal mucosa was always unmethylated. CRC patients with methylated p14(ARF). gene promoter had significantly worse prognosis (p=0.036), whereas those with methylated O-6-MGMT had significantly better prognosis through the first 60 months post-treatment (RR 0.36; p=0.023). Methylation of one or more of the genes from the set p14(ARF), RASSF1A and APC1A, was significantly (p=0.021) associated with worse prognosis even adjusting for tumor stage and differentiation (RR 2.2, p=0.037). Thus, DNA methylation of the p14(ARF), RASSF1A and APC1A genes, diagnosed by Pyrosequencing, defines a poor prognosis subset of CRC patients independently of both tumor stage and differentiation. O-6-MGMT methylation may play a protective role.
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