Edwin Cuppen

Pan-cancer landscape of homologous recombination deficiency

Abstract Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1 - and BRCA2 -subtypes. Analysis of a metastatic ( n  = 3,504) and primary ( n  = 1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1 , BRCA2 , RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2 -type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).