Differential DNA Methylation Profiles in Gynecologic Cancers

Abstract

CpG island hypermethylation of cancer-related genes is a frequent epigenetic event in human cancers. The present study was to determine the CpG island methylation profiles in gynecologic cancers; and to identify potential targets for cancer management. Methylation status for 34 loci was examined in differential DNA pools representing tumor and normal DNA from 50 cervical cancer, 50 endometrial cancer and 50 ovarian cancers by methylation specific polymerase chain reaction. Methylated alleles detected in tumor but not in normal DNA indicated the occurrence of aberrant methylation in tumors. Multiple genes were methylated in the three cancers. P16 and APC were methylated across the three cancers. MINT31 and PTEN were methylated in cervical and ovarian cancers. And RAR-β2 was methylated in ovarian and endometrial cancer. Specific methylation was also found in cervical cancer (including CDH1, DAPK, HIC-1, MGMT, MINT1, MINT2 and RASSF1A), in endometrial cancer (including CASP8, CDH13, hMLH1 and p73), and ovarian cancer (including BRCA1, p14, p15, RIZ1 and TMS1). Furthermore, incidence of methylation for DAPK, MGMT, p16 and PTEN in 127 cervical cancers; APC, CDH13, hMLH1 and p16 in 60 endometrial cancer; and BRCA1, p14, p16 and PTEN in 50 ovarian cancers, was determined. Incidence varied among different genes and in different cancer types ranging from the lowest 8.0% (PTEN in ovarian cancer) to the highest 56.7% (DAPK in cervical cancer). Methylation of some specific loci was related to particular tumor subtypes. In cervical cancer, DAPK methylation was more frequently detected in squamous cell carcinoma (SCC) than in adenocarcinoma (AC), whereas PTEN methylation was more frequent in AC than in SCC (P<0.01, respectively). And a significant correlation was observed between MGMT methylation and early-stage tumor (P=0.03). In ovarian cancer, methylation of BRCA1 was significantly associated with serous carcinoma, while PTEN was associated with mucinous carcinoma (P=0.02, respectively). And P14 methylation was more common in low-grade tumor (p=0.02) and early-stage tumor (P=0.04). In endometrial cancer, hMLH1 methylation was detected at a significantly higher frequency in high-grade tumor (P<0.01); p16 methylation was only present in stage I carcinoma (p=0.01). In addition, DAPK methylation was independently associated with shorter disease free survival by multivariate analysis and PTEN methylation was related to radiosensitivity in cervical cancer. Thus, differential methylation profiles occur in the three types of gynecologic cancers. Detection of methylation for critical loci is potentially useful as epigenetic markers in tumor classification, prognosis and predicting therapeutic response in gynecologic cancers.