OBJECTIVE: We analyzed the gene status of p16INK4A, p18INK4C, the expression of cell cycle associated proteins (p16INK4A, p18INK4C, cyclin D1, CDK4, pRb, and p53), and human papillomavirus (HPV) infection to investigate whether the inactivation of these genes participated in carcinogenesis, and to evaluated the expression of cell cycle associated proteins and HPV infections. METHODS: We examined forty-one primary cervical carcinomas (17 adenocarcinomas, 13 keratinizing squamous cell carcinomas, and 11 nonkeratinizing squamous cell carcinomas) using PCR, comparative multiplex PCR, PCR-SSCP, methylation-specific PCR, and immunohistochemistry. RESULTS: Ninety percent of cervical carcinomas showed HPV infection. HPV type 16 was detected in 41% and HPV type 18 was found in 44%. Homozygous deletions at p16INK4A gene were observed in 2 cases, but the mutation of p16INK4A and alterations of p18INK4C gene were not detected. The promoter hypermethylation for p16INK4A in nine cases (31%) of 29 cervical carcinomas was found. Expression of p16INK4A protein was observed in 93% and p18INK4C protein expression was noted in 78%. Positive immunostaining for cyclin D1 was only identified in 5%, whereas positive immunostaining for CDK4 was observed in 95%. Expression of pRb protein was found in 93% and p53 protein in 24% of cervical carcinomas. CONCLUSION: These results suggest that high risk HPV infections and methylation of the p16INK4A promoter region seem to play an important role in the pathogenesis of cervical carcinomas. Alterations of p18INK4C gene and cyclin D1-CDK4 pathway does not contribute significantly in the cervical carcinogenesis.
Adenocarcinoma ; Carcinogenesis ; Carcinoma, Squamous Cell ; Cell Cycle* ; Cyclin D1 ; Cyclin-Dependent Kinase Inhibitor p16 ; Cyclin-Dependent Kinase Inhibitor p18 ; Cyclins ; Genes, p16 ; Humans* ; Immunohistochemistry ; Methylation ; Multiplex Polymerase Chain Reaction ; Papillomavirus Infections* ; Polymerase Chain Reaction ; Promoter Regions, Genetic