Mutational and low-coverage whole genome sequencing identifies actionable DNA repair alterations in prostate cancer plasma DNA

PARP inhibitors (PARPi), recently introduced for treating metastatic castration-resistant prostate cancer (mCRPC), have heightened interest in molecular profiling for pathogenic aberrations in homologous recombination DNA repair (HRR) genes in all mCRPC patients. Liquid biopsy offers a viable alternative to archival tumor tissue for genetic analysis. In this study, we assessed the feasibility and utility of combining mutational panel sequencing with shallow whole genome sequencing (sWGS) to refine HRR status determination from plasma in prostate cancer (PCa) patients. The mutational profile of 16 HRR genes was assessed in 63 PCa patients: 28.6% of patients harbored putative pathogenic variants in HRR-related genes. A HRR-mutant status was defined for 10 patients (15.8%). Through the integration of sWGS data, plasma samples non-informative about somatic alterations were identified, and germline/somatic origin of HRR mutations was defined. Matched tumor tissue was available for 41 patients, with an 85.7% concordance rate between plasma and tissue mutational analyses. Additionally, we explored the copy number variation (CNV) profile using sWGS and it was found concordant with the literature PCa profiles. Our findings demonstrated that ctDNA analysis through liquid biopsy is a reliable alternative to tissue-based methods for identifying SNVs and CNVs. However, concordance was affected by ctDNA levels in plasma and clonal hematopoiesis. The data highlight the utility of integrating sWGS with targeted mutation analysis for comprehensive molecular profiling of PCa patients.