DNA hypermethylation status of multiple genes in prostate adenocarcinomas

Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 32 prostate adenocarcinomas not only for deletions and/or mutations of multiple suspect genes, but also for aberrant DNA methylation using methylation-specific PCR (MSP). Of those genes examined, p16 INK4a , O 6 -MGMT, and GST-P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14 ARF , RB1, p21 wafI , and p27 KipI were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O 6 -MGMT and GST-P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14 ARF and p16 INK4a genes (13% and 3% of cases, respectively). In p16 INK4α , methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O 6 -MGMT with concurrent p53 and ras gene mutations were found in 6% and 13% of specimens, respectively; among those tumors with high Gleason scores were 2 carcinomas showing hypermethylated O 6 -MGMT with G-to-A transitions in K-ras. Our results demonstrate that multiple genes of a subset common in prostate carcinomas are methylated and not infrequently show concurrent deletions. Further, there is a suggestion that specific combinations of hypermethylation and mutation correlate to tumor malignancy.