Alteration ofp16 andp15 genes in common epithelial ovarian tumors

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Abstract
We have examined the roles of 2 putative tumor‐suppressor genes, the p16 and p15 inhibitor‐of‐cyclin‐dependent‐kinase genes, in the most commonly occurring epithelial tumors of the human ovary. Expression of p16 mRNA, examined by RT‐PCR, was significantly reduced in 15 of the 48 tumors. Aberrant expression of p16 protein, detected by immunohistochemistry, occurred in 22 of 60 tumors, more frequently in low‐grade tumors, and had significant correlation with low p16 mRNA expression. Hypermethylation of a site within the 5′‐CpG island of the p16 gene was significantly associated with loss of p16 mRNA and protein expression. Homozygous gene deletion, evaluated by differential PCR analysis, was found in 2 tumors for the p16 gene and in 1 tumor for the p15 gene among 70 ovarian tumors examined. PCR‐SSCP analysis detected point mutations in p16 in 4 tumors and in p15 in 1 tumor. One was a 38‐bp deletion, from codons 48 to 60, in a mucinous tumor of low malignant potential; another was a non‐sense mutation in codon 60 in a mucinous adenocarcinoma. The remaining 2 mutations were mis‐sense mutations, one in codon 58 and the other in codon 60, in 2 endometrioid adenocarcinomas. We conclude that inactivation of p16, by loss of p16 mRNA and protein expression as a consequence of hypermethylation of the 5′‐CpG island, rather than by gene deletion or point mutation, may play an important role in the genesis of human ovarian epithelial tumors. Int. J. Cancer 74:148‐155, 1997. © 1997 Wiley‐Liss, Inc.