Promoter hypermethylation of multiple genes in carcinoma of the uterine cervix.

Promoter hypermethylation is an important pathway for the repression of gene transcription in cancer. We investigated promoter hypermethylation of six genes, p16, APC, HIC-1, death-associated protein kinase (DAPK), O(6)-methylguanine-DNA-methyltransferase (MGMT), and E-cadherin, in uterine cervical carcinoma from 53 patients including 31 cases of squamous cell carcinoma (SCC) and 22 cases of adenocarcinoma (AC). Aberrant methylation of at least one of these genes was detected in 79% (42 of 53) of cases including 71% (22 of 31) of SCC and 91% (20 of 22) of AC cases. No aberrant methylation was detected in normal cervical tissue from 24 control hysterectomy specimens. There was no correlation between promoter hypermethylation at any gene and the presence of human papillomavirus-16 or -18 E7 DNA. In AC cases, promoter hypermethylation of the APC and HIC-1 genes was detected at a statistically significant higher frequency than in the SCC cases (APC, 60% versus 13%, P < 0.001; HIC-1, 63% versus 32%, P < 0.03). Conversely, promoter hypermethylation of p16 and DAPK was more common in SCC cases than in AC cases. Our results suggest that promoter hypermethylation is a frequent epigenetic event in cervical carcinoma. The pattern of gene promoter hypermethylation is distinctly different between AC and SCC. The absence of these epigenetic alterations in normal cervical tissue suggests that they may also be valuable as cancer markers.