A meta-analysis of clinical cases of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance L. Tobalina1, J. Armenia1, E. Irving2, M. J. O’Connor2 and J. V. Forment2 1Bioinformatics and data science and 2DDR Biology, Bioscience; Oncology R&D, AstraZeneca, Cambridge, UK Background Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild type BRCA gene, which makes them exquisitely sensitive to platinum drugs and PARP inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. Patients We analyse published sequencing data of BRCA genes (from tumour or circulating tumour DNA) in 327 patients with tumours harbouring mutations in BRCA1 or BRCA2 (234 patients with ovarian cancer, 27 with breast cancer, 13 with pancreatic cancer, 11 with prostate cancer and 42 with a cancer of unknown origin) that progressed on platinum or PARPi treatment. Results We describe 269 cases of reversion mutations in 86 patients in this cohort (26.3%). Detailed analyses of the reversion events underlines the different importance of BRCA protein domains in contributing to resistance, as revertant proteins can be devoid of sizable parts of the original sequence. They also highlight the key role of mutagenic end-joining DNA repair pathways in generating reversions, especially in those affecting BRCA2. Conclusions Our analyses suggest that pharmacological inhibition of DNA end-joining repair pathways could improve durability of drug treatments by preventing the acquisition of reversion mutations in BRCA genes. They also highlight potential new therapeutic opportunities when reversions result in expression of hypomorphic versions of BRCA proteins, especially with agents targeting the response to DNA replication stress.