p16/MTS1 inactivation in ovarian carcinomas: high frequency of reduced protein expression associated with hyper-methylation or mutation in endometrioid and mucinous tumors.
Inactivation of the tumor-suppressor gene p16 (MTS1/ CDKN2/INK4a) has been described in various human malignancies. Although p16 deletion has been found in various ovarian tumor cell lines, p16 inactivation by homozygous 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. Loss of expression was detected in 19 primary tumors (20%), mainly mucinous and endometrioid carcinomas. To reveal the cause of suppressed expression, we performed (i) analysis of homozygous deletions by comparative PCR after micro-dissection, (ii) mutation analysis by single-strand conformation polymorphism analysis and subsequent direct sequencing and (iii) methylation-specific PCR to determine the methylation status of 5'-CpG islands. Loss of or weak p16 expression was caused by hyper-methylation (12/19 IHC-negative cases), somatic mutation (10 tumors) or homozygous deletion (1 case). Aberrant p 16 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 inactivation is a typical feature of certain subtypes of ovarian carcinoma.
Milde-Langosch
K
K
Department of Gyneco-pathology, University Clinics of Obstetrics and Gynecology, Hamburg, Germany.
Ocon
E
E
Becker
G
G
Löning
T
T
D002288:Adenocarcinoma, Mucinous / Q000235:genetics*; D000368:Aged; D002277:Carcinoma / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018283:Cystadenocarcinoma, Papillary / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm