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Genetic Versus Epigenetic BRCA1 Silencing Pathways: Clinical Effects in Primary Ovarian Cancer Patients
  1. Tingting Sun*,
  2. Ilary Ruscito, MD*,,,
  3. Desislava Dimitrova, MD*,
  4. Radoslav Chekerov, MD*,
  5. Hagen Kulbe, PhD*,
  6. Udo Baron, PhD§,
  7. Véronique Blanchard, PhD,
  8. Pierluigi Benedetti Panici, MD, PhD,
  9. Silvia Darb-Esfahani, MD, PhD,
  10. Jalid Sehouli, MD, PhD*,
  11. Sven Olek, PhD§ and
  12. Elena Ioana Braicu, MD, PhD*
  1. *Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany;
  2. Department of Gynecology, Obstetrics, and Urology,
  3. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy;
  4. §Ivana Türbachova Laboratory for Epigenetics, Epiontis GmbH, Berlin, Germany;
  5. Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité Medical University, Berlin, Germany; and
  6. Institute of Pathology, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  1. Address correspondence and reprint requests to Elena Ioana Braicu, Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: Elena.Braicu@charite.de.

Abstract

Objectives The aim of the present study was to assess in a large cohort of primary epithelial ovarian cancer patients the incidence and the clinical effect of BRCA1 genetic and epigenetic silencing mechanisms.

Methods A total of 188 primary epithelial ovarian cancer patients, treated between 2000 and 2011 at the Charité University Hospital of Berlin, were included. The patients' tumor and blood samples were obtained from the Tumor Bank Ovarian Cancer Network (www.toc-network.de). Direct sequencing of BRCA1 exon 11 was performed to detect germline mutations, whereas tumor samples were assessed for BRCA1 promoter hypermethylation by bisulphite-converted methylation-specific polymerase chain reaction. Basing on their BRCA1 status, patients were compared regarding clinicopathological variables and survival.

Results Twenty-one patients (11.2%) showed hypermethylation in BRCA1 promoter (HMB), and 18 patients (9.6%) presented germline mutations in BRCA1 exon 11 (GMB). Patients with HMB showed a significantly younger age at diagnosis compared with BRCA1 wild type (BWT) patients (54 vs 61 years, P = 0.045), and both GMB and HMB patients were more likely to have high-grade serous ovarian cancer (76.2% and 77.8% vs 52.7%, P = 0.043 and P = 0.043). Positive family history of breast or ovarian cancer (OC) was more frequently reported among GMB patients with respect to BWT patients (44.4% vs 13.5%, P = 0.003); GMB, HMB, and BWT patients did not show significant differences in terms of tumor dissemination pattern, surgical outcomes, platinum response or survival; neither mutational nor hypermethylation BRCA1 status was found to be an independent prognostic factor for OC patients.

Conclusions Hypermethylation in BRCA1 is associated with earlier occurrence of OC. In addition, the coexistence of both GBM and HMB is an infrequent event, occurring in 0.5% of OC cases. Silencing of BRCA1 through mutation and hypermethylation confers to distinct clinical characteristics of OC patients but similar clinical outcome with respect to BWT patients.

  • Ovarian cancer
  • BRCA1
  • Hypermethylation
  • Germline mutation
  • Outcome
  • Survival
  • BWT-BRCA1 wide type
  • BC/OC-breast cancer or ovarian cancer
  • CI-confidence intervals
  • GMB-germline mutations in BRCA1 exon 11
  • HGSOC-high-grade serous ovarian cancer
  • HMB-hypermethylation of BRCA1 promoter
  • HR-hazard ratios
  • LGSOC-low-grade serous ovarian cancer
  • OS-overall survival
  • PEOC-primary epithelial ovarian cancer
  • PARP-Poly (ADP-ribose) Polymerase
  • PFS-progression-free survival

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Footnotes

  • This study was partially supported through a research grant from Berliner Krebsgesellschaft. The financial support was used to provide the reagents and document the clinical data. Elena Ioana Braicu, MD, PhD, is a participant of the Charité Clinical Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.

  • The authors declare no conflicts of interest.

  • Tingting Sun and Ilary Ruscito contributed equally to this work.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

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