BackgroundHomologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.ResultsUsing whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.ConclusionOur results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.

Prostate adenocarcinoma cases with homologous recombination deficiency (HRD) benefit from PARP inhibitor therapy. Currently, direct sequencing of a handful of key homologous recombination genes serves as an indicator of HRD in prostate cancer. It is well known, however, that other mechanisms, such as suppression of expression of HR-related genes can also cause HRD, but the detection of those in biological samples is often difficult due to e.g. normal tissue contamination. Here we show that in 5-10% of localized prostate adenocarcinoma cases whole genome sequencing data display homologous recombination deficiency associated mutational signatures even in the absence of loss of function mutations in BRCA1/2 or other canonical homologous recombination genes. These cases may also be sensitive to PARP inhibitor or platinum-based therapy. Extending PARP inhibitor therapy to all cases with HRD-associated mutational signatures, even to those without BRCA1/2 mutations, may increase the efficacy of this treatment.