Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Background/Aim: Approximately 20 – 25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination (HR) pathway. Inactivation of these genes can also be mediated by epigenetic changes e.g. hypermethylation of CpG islands in the promoter regions. Aim of this analysis was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy.

Methods: 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer were included. Following primary surgery all patients received firstline platinum-based chemotherapy. In a subgroup of 12 patients 'paired' tumour tissue from primary and recurrent surgery was available. DNA was extracted from fresh frozen tumour tissue and BRCA1 promoter methylation rate was assessed using methylation specific polymerase chain reaction (MS-PCR). Results were verified by Sanger Sequencing.

Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumours displayed BRCA1 promoter hypermethylation. Neither in the primary nor the recurrent situation, BRCA1 promoter methylation status was 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 tumours showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed whereas two had stable methylation status. No tumour showed a gain of BRCA1 promoter hypermethylation.

Conclusion: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, clinical significance especially regarding response to polyadenosine diphosphate [ADP]-ribose polymerase inhibitors (PARPi) is unclear and should be evaluated in prospective clinical trials.