Abstract P080: Analysis of clinical BRCA1/2 reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance

Abstract

Abstract Although PARP inhibitors and platinum salts form part of the standard-of-care for cancers with homologous recombination (HR) defects, drug resistance does emerge and is often caused by reversion mutations in BRCA1 or BRCA2. Reversion mutations are secondary mutations that restore functional protein or compensate for frameshift mutations. To better understand the nature and aetiology of these mutations, we collated, codified and analysed over 200 reversion mutations from 24 published studies. Most reversions have been reported as case reports or small clinical series – we have collected all published reports into a single freely-accessible database to which further cases can be submitted. The majority of reported reversion mutations are from BRCA1/2 mutant serous ovarian cancer, reflecting the longer use of platinum and PARP inhibitors in this disease. Our analysis identified reversion “hotspots” and “deserts” in the N- and C-terminal coding regions (respectively) of BRCA2, suggesting that pathogenic mutations in these domains may be at higher or lower chance of reversion, an effect not seen for BRCA1. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than frameshift-causing mutations. Unexpectedly, whilst most reversions were <100 bp “second site” deletions, microhomology use was not universal, especially in BRCA1-mutant cancers, suggesting that multiple DNA repair processes cause reversion and these vary in BRCA1 vs. BRCA2 mutant tumours. Reversions in BRCA1 mutant tumours were less likely to be mediated by deletions. Many reversions contain novel protein sequence not found in the wild type protein, for example where a stretch of out-of-frame protein sequence is retained between the pathogenic and reversion mutations. We modelled MHC binding affinities for these sequences and found that many reversions were predicted to encode potentially immunogenic neopeptides, suggesting a route to the treatment of reverted disease. These observations have implications for how drug resistance might be managed in BRCA-mutant cancers. Citation Format: Stephen J. Pettitt, Jessica Frankum, Marco Punta, Stefano Lise, John Alexander, Yi Chen, Syed Haider, Andre N. J. Tutt, Christopher J. Lord. Analysis of clinical BRCA1/2 reversions identifies hotspot mutations and predicted neoantigens associated with therapy resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P080.