A meta-analysis of clinical cases of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance

Germline mutations in the or genes predispose to hereditary breast and ovarian cancer and, mostly in the case of , are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild type 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 mechanisms of resistance to these treatments. Here, we perform a detailed analysis of clinical cases of reversion mutations described in and , which underlines the different importance of BRCA protein domains in contributing to resistance and the potential key role of mutagenic end-joining DNA repair pathways in generating reversions. Our analyses suggest that pharmacological inhibition of these repair pathways could improve durability of drug treatments and highlights potential interventions to both prevent the appearance of reversions and provide new therapeutic opportunities after their acquisition.