P16 OVEREXPRESSION - A POTENTIAL EARLY INDICATOR OF TRANSFORMATION INOVARIAN-CARCINOMA

OBJECTIVE: The recently cloned gene p16 (MST1) has been identified as a putative tumor suppressor gene that binds to CDK4 and CDK6 (cyclin-d ependent kinases), preventing their interaction with cyclin D1 and the reby preventing cell cycle progression at the G1 stage. In addition, t he p16 gene has been shown to have a high frequency of mutation in som e tumor cell lines; however; it has also been shown that a much lower frequency of mutation occurs in primary tumors. This study investigate d the mRNA expression level and mutation status of the p16 gene in ova rian tumors. METHODS: We performed quantitative polymerase chain react ion and direct cDNA sequencing analysis. To confirm the p16 protein le vel in ovarian tumors, Western blotting and immunohistochemical staini ng were performed. Expression levels of mRNA for the p16 gene relative to the beta-tubulin gene were examined in 32 ovarian tumors (24 carci nomas, six low malignant potential tumors, and two benign tumors) and six normal ovaries. RESULTS: The mRNA expression level of p16 was sign ificantly elevated in 28 ovarian tumors (22 carcinomas, jive low malig nant potential tumors, and one benign tumors) compared with that of no rmal ovaries. Western blotting analysis and immunohistochemical staini ng confirmed elevated p16 protein levels in ovarian tumor samples. Amo ng 32 ovarian tumors, cDNA sequencing of rite p16 gene showed no p16 m utation resulting in a coding error, although one silent incitation an d three polymorphisms were found. CONCLUSIONS: Although p16 is seldom mutated in ovarian tumors, the overexpression of p16 in most ovarian t umor cases indicates a dysfunction in the regulatory complex for G1 ar rest. Therefore, overexpression of p16 may be an important early event in the neoplastic transformation of the ovarian epithelium. Copyright (C) 1997 by the Society for Gynecologic Investigation.