Correlation of promoter hypermethylation in hTERT, DAPK and MGMT genes with cervical oncogenesis progression

Abstract

DNA hypermethylation occurs during the multi-step process of cervical carcinogenesis. We investigated whether the methylation status in the promoter region of a potential oncogene, the human telomerase reverse transcriptase (hTERT), and the tumor suppressor genes death-associated protein kinase (DAPK) and O(6)-methylguanine DNA methyltransferase (MGMT), were able to distinguish the early from late stages of cervical oncogenesis. The methylation status in the promoter of these genes was analyzed using real-time MethyLight analysis in 115 cervical specimens, including normal, premalignant [atypical squamous epithelial cells (ASCUS), low-grade squamous intraepithelial lesions (LGSIL), high-grade squamous intraepithelial lesions (HGSIL)] and cancer specimens. Clinicopathological parameters (cytology, histology, grade, stage) were compared to the levels of pro-moter hypermethylation. We found that hTERT, MGMT and DAPK hypermethylation levels were increased during cervical oncogenesis progression. hTERT promoter hypermethylation was able to distinguish normal from cancer (p=0.008), normal from premalignant (p=0.036), its well as premalignant from cervical cancer cases (p=0.003). A significant association was also observed between all three genes and the grade of cervical cancer, with hTERT showing a better association (p<0.0001). Our data suggest that the combination of hTERT, MGMT, DAPK promoter hypermethylation could have a potential function as molecular biomarker of cervical oncogenesis progression.