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

Background: Approximately 20-25% of ovarian cancers are attributable to germline or somaticBRCA1/2mutations, 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 ofBRCA1promoter 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.BRCA1promoter 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 displayedBRCA1promoter hypermethylation.BRCA1promoter 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 ofBRCA1hypermethylation was observed, whereas two patients had stable methylation status.

Conclusions: Loss ofBRCA1promoter methylation may be a mechanism to restoreBRCA1function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.