Promoter hypermethylation of CDH13, DAPK1 and TWIST1 genes in precancerous and cancerous lesions of the uterine cervix

Abstract

Aberrant DNA methylation is an early event in carcinogenesis and could serve as an additional molecular marker for the early diagnosis. The study was performed to investigate the promoter methylation of DAPK1, CDH13, and TWIST1 genes in uterine cervix lesions in an effort to examine whether this epigenetic event is involved in the process of cervical carcinogenesis, and whether it might be used as a molecular marker of cervical lesions. We conducted a retrospective study of 60 uterine cervix specimens, including 8 normal tissue samples, 10 benign lesions, 28 precancerous lesions (CIN1-3), and 14 squamous cell carcinomas (SCC). DNA hypermethylation was investigated using methylation-specific PCR. Immunohistochemistry was used to find p16(INK4A) overexpression. No hypermethylated promoters were detected in normal tissues and benign lesions. However, promoter hypermethylation of CDH13, TWIST1, and DAPK1 increased progressively from CIN1 to cancer, reaching values higher than 50% for cancer. DAPK1 and CDH13 displayed a significantly increased frequency of promoter methylation with progressively more severe cervical neoplasia (p<0.05). A statistically significant association was observed between p16(INK4A) expression and hypermethylation of DAPK1, TWIST1, and CDH13 (p<0.0001). Hypermethylation of CDH13, DAPK1, and TWIST1 promoters is an early event in the initiation and progression of cervix neoplasia. CDH13, DAPK1, and TWIST1 genes are potential biomarkers of cervical cancer risk.