Role of BRCA1 promotor methylation (BRCA1meth) in homologous recombination deficiency (HRD) in high-grade epithelial ovarian cancer.

Abstract

e17592 Background: In TCGA data BRCA1meth was found to be inferior to BRCAmut regarding prognosis in high-grade ovarian cancer. This was explained by a probably lower sensitivity to platinum-based chemotherapy. Methods: In 151 high-grade epithelial ovarian cancers (HGOC) tested for BRCA status, BRCA DNA methylation was determined using MethyLight PCR. Additionally, genome-wide loss of heterozygosity (LOH) and Aneuploidy Normalized Telemetric imbalance (ANTI) by means of SNP-Array analysis (GSA-24 v 3.0/Ilumina) as surrogates for “genomic scaring” in BRCA-independent HRD. For both parameters a “clinical-threshold” was calculated on the basis of platinum-response determined at the first recurrence according to the platinum-free interval. Both variables were integrated in a common HRD-Score with a cut-off value of ≥ 10.3 for HRD positivity. Results: In the present cohort PFS of BRCA1meth HGOC (n = 15; 10%) was not revealed to be inferior to BRCAmut HGOC. Worst PFS was observed in the subgroup of BRCAwt-unmethylated HGOC (p = 0.013) as compared to HGOC with genetic and epigenetic BRCA alterations. In line, neither LOH nor ANTI and consecutively also HRD-Score did prove to be statistically different in BRCAmut - and BRCA1meth-HGOC. However, BRCAwt-unmethylated HGOC exhibited significantly lower HRD-, LOH- and ANTI-Scores when compared with BRCAmut (p < 0.001) and BRCA1meth-HGOC (p < 0.005). All but one of the HGOC classified as platinum-refractory or -resistant at first relapse (92%) were BRCAwt-unmethylated. None of the BRCA1meth cancers were rated platinum-refractory or -resistant at progression and only one of the BRCAmut cancers was associated with platinum-resistant first relapse. 99% of the recurrences from HGOC with genetically or epigenetically altered BRCA genes were platinum sensitive, from which 78% were classified as “high-sensitive”. In multivariate analysis, HRD-Score was found to be of independent prognostic significance regarding PFS (p = 0.022); this was mainly due to the prognostic power of ANTI-Score (multivariate: p = 0.014) but not to that of genome wide LOH (univariate: p = 0.771). Conclusions: HGOC without genetic or epigenetic BRCA alterations exhibit the most unfavorable PFS. This is related to impaired platinum sensitivity. From a clinical point of view BRCA1 promotor methylation seems to confer an equivalent detrimental effect on the homologous recombination DNA repair mechanism than do pathogenic mutations of the BRCA genes. This is corroborated by a nearly identical extent of genome-wide scaring in both cancer subgroups.