Oncotarget

Research Papers:

Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer

Katharina Prieske _, Stefan Prieske, Simon A. Joosse, Fabian Trillsch, Donata Grimm, Eike Burandt, Sven Mahner, Barbara Schmalfeldt, Karin Milde-Langosch, Leticia Oliveira-Ferrer and Linn Woelber

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Oncotarget. 2017; 8:83063-83074. https://doi.org/10.18632/oncotarget.20945

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Abstract

Katharina Prieske1,*, Stefan Prieske1,*, Simon A. Joosse2, Fabian Trillsch3, Donata Grimm1, Eike Burandt4, Sven Mahner3, Barbara Schmalfeldt1, Karin Milde-Langosch1, Leticia Oliveira-Ferrer1 and Linn Woelber1

1Department of Gynecology and Gynecologic Oncology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

2Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

3Department of Gynecology and Obstetrics, University of Munich, 81377 Munich, Germany

4Department of Pathology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany

*These authors have contributed equally to this work

Correspondence to:

Katharina Prieske, email: k.prieske@uke.de

Keywords: BRCA methylation, ovarian cancer, platinum, recurrence, high-grade

Received: May 30, 2017    Accepted: July 25, 2017    Published: September 15, 2017

ABSTRACT

Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy.

Methods: Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, ‘paired’ tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing.

Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free- or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status.

Conclusions: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.


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