ALTERATION OF P16 AND P15 GENES IN COMMON EPITHELIAL OVARIAN-TUMORS

We have examined the roles of 2 putative tumor-suppressor genes, the p 16 and p15 inhibitor-of-cyclin-dependent-kinase genes, in the most com monly occurring epithelial tumors of the human ovary. Expression of p1 6 mRNA, examined by RT-PCR, was significantly reduced in 15 of the 48 tumors. Aberrant expression of p16 protein, detected by immunohistoche mistry, occurred in 22 of 60 tumors, more frequently in low-grade tumo rs, and had significant correlation with low p16 mRNA expression. Hype rmethylation of a site within the 5'-CpG island of the p16 gene was si gnificantly associated with loss of p16 mRNA and protein expression. H omozygous gene deletion, evaluated by differential PCR analysis, was f ound in 2 tumors for the p16 gene and in 1 tumor for the p15 gene amon g 70 ovarian tumors examined. PCR-SSCP analysis detected point mutatio ns 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 adenocarci noma. The remaining 2 mutations were mis-sense mutations, one in codon 58 and the other in codon 60, in 2 endometrioid adenocarcinomas. We c onclude that inactivation of p16 by loss of p16 mRNA and protein expre ssion as a consequence of hypermethylation of the 5'-CpG island, rathe r than by gene deletion or point mutation, may play an important role in the genesis of human ovarian epithelial tumors. (C) 1997 Wiley-Liss , Inc.