P16 MTS1 INACTIVATION IN OVARIAN CARCINOMAS - HIGH-FREQUENCY OF REDUCED PROTEIN EXPRESSION ASSOCIATED WITH HYPER-METHYLATION OR MUTATION INENDOMETRIOID AND MUCINOUS TUMORS/

Inactivation of the tumor-suppressor gene p16 (MTSI/CDKN2/INK4a) has b een described in various human malignancies. Although p16 deletion has been found in various ovarian tumor cell lines, p16 inactivation by h omozygous deletion or mutation has been reported only sporadically in primary ovarian carcinomas, In a comprehensive study, we analyzed p16 protein expression by immuno-histochemistry (IHC) on paraffin sections of 94 primary ovarian carcinomas of different histological subtype. L oss of expression was detected in 19 primary tumors (20%), mainly muci nous and endometrioid carcinomas. To reveal the cause of suppressed ex pression, we performed (i) analysis of homozygous deletions by compara tive PCR after micro-dissection, (ii) mutation analysis by single-stra nd conformation polymorphism analysis and subsequent direct sequencing and (iii) methylation-specific PCR to determine the methylation statu s of 5'-CpG islands. Loss of or weak p16 expression was caused by hype r-methylation (12/19 IHC-negative cases), somatic mutation (10 tumors) or homozygous deletion (1 case). Aberrant p16 results by one of these methods were detected in 71-79% of endometrioid and mucinous, but in only 10% of serous-papillary, carcinomas. Our data suggest that p16 in activation is a typical feature of certain subtypes of ovarian carcino ma. (C) 1998 Wiley-Liss, Inc.