Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

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.

BRCA1Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis

“…Moreover, tissue sampling size and content introduces bias owing to variations in sampling sites (ovary versus metastatic), neoplastic cell content and intratumor heterogeneity. Four studies report particularly high BRCA1 methylation rates: 21.4% 35 , 33.6% 16 , 42% 39 and 73.7% 43 . This latter cohort, which confirmed all its MSP-GE determined BRCA1-methylated OC cases with Sanger sequencing, consisted solely of relapsed cases, which may account to some extent for this variation.…”

“…Potentially, chemotherapy induces changes affecting the methylation levels of the BRCA1 promoter, causing earlier and perhaps more frequent resistance to platinum-based chemotherapy than is observed in BRCA1-mutated OC. This may manifest as methylation loss in relapsed BRCA1-methylated OC, observed in 16.7% -80.0% of small mostly retrospective cohorts of 6 to 13 paired primary/recurrent BRCA1-methylated HGSC 43,52,54,55 .…”

“…One author provided data on additional patients not included in the original publication. Overall, 15 observational studies (430 cases; 2206 controls) were included 3,13,15,16,[35][36][37][38][39][40][41][42][43] (Supplementary Tables 2 -4).…”

Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma

“…However, many recent studies do not support these findings [20][21][22][23] . In some cases, methylated BRCA1 in tumors was found to be demethylated after chemotherapy 24,25 . The presence of BRCA1 methylation before treatment was associated with post relapse platinum resistance in a study of triple-negative breast cancer 26 .…”

BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer

“…Although hypermethylation of the BRCA1 promoter has been shown in xenografts to predict response to PARP inhibitors as well [8], data on patient survival are still unclear [9]. Recently, we showed that the BRCA1 promoter is frequently hypermethylated in ovarian cancer tissue, but the methylation status is often lost in recurrent disease, suggesting a potential resistance mechanism either through therapy-induced cancer evolution or by clonal selection [10][11][12]. Thereby, the detection and monitoring of BRCA1 promoter hypermethylation may have an important impact on the clinical management of ovarian cancer patients without BRCA1 mutation [8].…”