Reversion mutations define minimal BRCA1/2 requirements for therapy resistance

Abstract

Although platinum salts or PARP inhibitors are effective in delivering anti-tumor responses in people with BRCA1 or BRCA2 mutated cancers, drug resistance is common and is often caused by secondary BRCA1/2 reversion mutations that restore function. By collating and analyzing 848 BRCA1/2 reversion mutations in 384 cancer patients with drug resistance, we confirm that pathogenic BRCA1/2 mutation type influences the acquisition of reversions, and that large BRCA1/2 deletions are an underappreciated form of reversion. Integrating reversion data with systematic CRISPR-Cas9 screens that delete BRCA1/2 exons, we also show that both proteins contain privileged domains whose structure is essential for drug resistance, including the PALB2 interacting domains of both BRCA1 and BRCA2. Reversions in PALB2 also conserve both BRCA1 and BRCA2 binding domains. Surprisingly, exon 11 of BRCA2, which encodes BRC repeats 1-8, is not essential for resistance. Using this patient and functional information, we estimate the likelihood of pathogenic BRCA2 mutations to revert. We show that risk of reversion correlates with both the presence of clinical reversions and the response to treatment, suggesting that the propensity to revert could be a useful clinical parameter.