title: Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer.
abstract: BACKGROUND
  An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes.
  
  
  METHODS
  One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique.
  
  
  RESULTS
  Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05).
  
  
  CONCLUSIONS
  We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. gabriel.schmid@i-med.ac.at.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Schmid
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. sara.notaro@hotmail.it.|Department of Gynecology and Obstetrics, University of Brescia, Piazza Spedali Civili 1, 25123, Brescia, Italy. sara.notaro@hotmail.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Notaro
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. daniel.reimer@i-med.ac.at.
authors.forename: Daniel
authors.initials: D
authors.lastname: Reimer
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. Samira.Abdel-Azim@i-med.ac.at.
authors.forename: Samira
authors.initials: S
authors.lastname: Abdel-Azim
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. michaela.peer@i-med.ac.at.
authors.forename: Michaela
authors.initials: M
authors.lastname: Duggan-Peer
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. jessica.holly@i-med.ac.at.
authors.forename: Jessica
authors.initials: J
authors.lastname: Holly
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. Heidelinde.Fiegl@i-med.ac.at.
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. julia.roessler@uki.at.
authors.forename: Julia
authors.initials: J
authors.lastname: Rössler
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. annemarie.wiedemair@uki.at.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Wiedemair
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. nicole.concin@i-med.ac.at.
authors.forename: Nicole
authors.initials: N
authors.lastname: Concin
authors.affiliation: Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. p.altevogt@dkfz-heidelberg.de.|Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. p.altevogt@dkfz-heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. Christian.MARTH@tirol-kliniken.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Marth
authors.affiliation: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. alain.zeimet@uki.at.
authors.forename: Alain Gustave
authors.initials: AG
authors.lastname: Zeimet
mesh_terms: D000368:Aged; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D010053:Ovary / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs