title: HERV-K hypomethylation in ovarian clear cell carcinoma is associated with a poor prognosis and platinum resistance.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gynecologic Oncology Division, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Kanokwan
authors.initials: K
authors.lastname: Iramaneerat
authors.forename: Prakasit
authors.initials: P
authors.lastname: Rattanatunyong
authors.forename: Nipon
authors.initials: N
authors.lastname: Khemapech
authors.forename: Surang
authors.initials: S
authors.lastname: Triratanachat
authors.forename: Apiwat
authors.initials: A
authors.lastname: Mutirangura
mesh_terms: D000328:Adult; D015415:Biomarkers; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010984:Platinum / Q000494:pharmacology; D011379:Prognosis; D015183:Restriction Mapping; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D010984:Platinum