DNA Hypermethylation Status of Multiple Genes in Prostate Adenocarcinomas

• Published in: Cancer science 2002-07, Vol.93 (7), p.767-773
• Main Authors: Konishi, Noboru, Nakamura, Mitsutoshi, Kishi, Munehiro, Nishimine, Masayoshi, Ishida, Eiwa, Shimada, Keiji
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Biological and medical sciences; Carcinogenesis; CpG Islands; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-dependent kinase inhibitor p21; Cyclin-dependent kinase inhibitor p27; Deoxyribonucleic acid; DNA; DNA Methylation; DNA-Binding Proteins - genetics; Exons; Gene; Gene Deletion; Genes, p53 - genetics; Genes, Tumor Suppressor; Glutathione Transferase - metabolism; Guanosine - analogs & derivatives; Humans; INK4a protein; Male; Malignancy; Medical sciences; Methylation; Mutation; Nephrology. Urinary tract diseases; Nuclear Proteins - genetics; p16 Protein; p53 Protein; Polymerase Chain Reaction; Promoter Regions, Genetic; Prostate; Prostate carcinoma; Prostatic Neoplasms - genetics; Ras protein; Tumor Protein p73; Tumor Suppressor Protein p14ARF - genetics; Tumor Suppressor Proteins; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.2002.tb01318.x

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, p16INK4a, O6‐MGMT, and GST‐P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14ARF, RB1, p21waf1, and p27Kip1 were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O6‐MGMT and GST‐P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14ARF and p16INK4a genes (13% and 3% of cases, respectively). In p16INK4a, methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O6‐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 O6‐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.