HERV-K Hypomethylation in Ovarian Clear Cell Carcinoma Is Associated With a Poor Prognosis and Platinum Resistance

Abstract

In general, ovarian clear cell carcinoma (OCCC) has a history of poor response to standard platinum-based chemotherapy regimens, and advanced cases have short survival periods. Therefore, the discovery of a biomarker for the pretreatment prediction of OCCC is crucial. Loss of methylation of a retrotransposable sequence, such as long interspersed repetitive sequence 1 (LINE-1), frequently occurs in cancers, including ovarian cancer, and it has been proven to be associated with poor survival. The expressions of human endogenous retrovirus (HERV) K and E were found to be increased in tissues from patients with OCCC. Here, we propose that methylation levels of HERV are associated with treatment response and prognosis of OCCC. Twenty-nine patients with OCCC were enrolled. Methylation levels of HERV-K, HERV-E, and LINE-1 were measured from microdissected cancer and normal ovarian tissues. The methylation levels were correlated with stage, treatment response, and prognosis. Methylation levels of HERV-K, HERV-E, and LINE-1 were decreased in tissues from patients with advanced stage cancer (P = 0.0179, P = 0.0021, and P = 0.0307, respectively). Human endogenous retrovirus K demonstrated significantly lower methylation levels in the platinum-resistant group (P = 0.0004). Patients with lower levels of methylated (hypomethylated) HERV-K had a shorter mean overall survival (P = 0.006). In advanced OCCC cases, patients with hypomethylated HERV-K had shorter mean progression-free survival (P = 0.018) and mean overall survival (P = 0.018) than did patients with higher methylation levels of HERV-K. Methylation levels of HERV-K, HERV-E, and LINE-1 are decreased during OCCC multistep carcinogenesis. Moreover, HERV-K hypomethylation is a promising biomarker for predicting OCCC treatment response and prognosis.