title: BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients--a study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD).
abstract: BACKGROUND
  Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients.
  
  
  METHODS
  The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR).
  
  
  RESULTS
  14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽ 58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations.
  
  
  CONCLUSIONS
  Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany; Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Ruscito
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Dimitrova
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Vasconcelos
authors.affiliation: Ivana Türbachova Laboratory for Epigenetics, Epiontis GMBH, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Gellhaus
authors.affiliation: Ivana Türbachova Laboratory for Epigenetics, Epiontis GMBH, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schwachula
authors.affiliation: Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Bellati
authors.affiliation: Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Zeillinger
authors.affiliation: Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Benedetti-Panici
authors.affiliation: Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, UZ Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Vergote
authors.affiliation: Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Mahner
authors.affiliation: Ivana Türbachova Laboratory for Epigenetics, Epiontis GMBH, Berlin, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Cacsire-Tong
authors.affiliation: Department of Gynecology and Obstetrics, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Concin
authors.affiliation: Institute of Pathology, Charite Medical University, Berlin, Campus Mitte, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: Division of Gynaecological Oncology, Department of Obstetrics and Gynaecology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, UZ Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: Ivana Türbachova Laboratory for Epigenetics, Epiontis GMBH, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Olek
authors.affiliation: Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. Electronic address: elena.braicu@charite.de.
authors.forename: E I
authors.initials: EI
authors.lastname: Braicu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D019398:Genes, BRCA1; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA
keywords: BRCA1; Gene promoter; High grade serous ovarian cancer; Methylation; Prognosis