title: Evaluation of folate receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers.
abstract: In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer.
  
  
  
  Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique.
  
  
  
  No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers (p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS (p = 0.026) and OS (p = 0.012).
  
  
  
  No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours.
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.|Department of Gynecology and Obstetrics, University of Brescia, P.zza Spedali Civili 1, 25123, Brescia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Notaro
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reimer
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Schmid
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Annamarie
authors.initials: A
authors.lastname: Wiedemair
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Rössler
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. Alain.Zeimet@i-med.ac.at.
authors.forename: Alain Gustave
authors.initials: AG
authors.lastname: Zeimet
mesh_terms: D000368:Aged; D019175:DNA Methylation; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D010984:Platinum / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D010984:Platinum
keywords: FOLR1; FOLR1 promoter methylation; Folate receptor 1; Global DNA hypomethylation; Ovarian cancer; Platinum sensitivity; Type I; Type II