Finding novel vulnerabilities of hypomorphic BRCA1 alleles

With the recent rise in CRISPR/Cas9-mediated genome-wide synthetic lethality screens, many new synthetic lethal targets have been identified for diseases with underlying genetic causes such as tumours withBRCA1mutations. Such screens often use full deficiency of a protein to identify novel vulnerabilities. However, patient-derived mutations not only result in loss of the protein but often also concern missense mutations with hypomorphic phenotypes. Here we study the genetic vulnerabilities of two previously described hypomorphic BRCA1 missense mutations and compare these to a BRCA1-depleted setting to study whether this affects screening for synthetic lethal interactions. Our research showed that BRCA1^I26Amutated cells have very similar vulnerabilities to BRCA1 wildtype cells, confirming its low tumorigenic effect. In contrast, the BRCA1^R1699Qmutation induced a more similar phenotype to BRCA1-deficient cells. For this mutation, we also unveiled a unique vulnerability to the loss of NDE1. Specifically in BRCA1^R1699Qmutated cells, and not BRCA1-proficient or -deficient cells, NDE1 loss leads to increased genomic instability. Altogether our findings highlight the importance to differentiate between patient-derived mutations when assessing novel treatment targets.