Aberrant transcript usage induces homologous recombination deficiency and predicts therapeutic responses

ABSTRACT BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors causing low precision in predicting samples that will respond to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA damaging agents. Here, we present molecular evidence and clinical utility of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Our functional assays validated its association with impaired HR activity. Remarkably, tHRD detection based on the TU pattern of key genes was superior to gHRD or BRCA1/2 screening in accuracy for predicting the responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. In particular, this approach demonstrated the capability to reflect functional HR status, particularly when applied to our cohort of olaparib users with acquired platinum resistance in ovarian cancer. Hence, the tHRD-based diagnostic tests are expected to broaden the clinical utility of PARP inhibitors.