Genetic landscape of homologous recombination repair genes in early-onset/familial prostate cancer patients

Abstract Prostate cancer (PrCa) is among the three top most frequent and deadlier cancers worldwide. The discovery of PARP inhibitors for the treatment of tumors having deleterious variants in homologous recombination repair (HRR) genes has placed PrCa in the roadmap of precision medicine. Still, the overall contribution of HRR genes for the 10-20% of the carcinomas arising in men with early-onset/familial PrCa has not been fully clarified. We used Targeted Next Generation Sequencing (T-NGS) covering eight HRR genes ( ATM , BRCA1 , BRCA2 , BRIP1 , CHEK2 , NBN , PALB2 and RAD51C ) and an analysis pipeline querying both small and large genomic variations, to clarify both their global and relative contribution for hereditary PrCa predisposition in a series of 462 early-onset/familial PrCa cases. Deleterious variants were found in 3.9% of the patients, with CHEK2 and ATM being the most frequently mutated genes (38.9% and 22.2% of the carriers, respectively), followed by PALB2 and NBN (11.1% of the carriers, each), and then by BRCA2 , RAD51C , and BRIP1 (5.6% of the carriers each). Using the same NGS data, exonic rearrangements were found in two patients, one pathogenic in BRCA2 and one of unknown significance in BRCA1 . Additionally, 5.4% of the patients were carriers of variants of unknown significance (VUS). These results support the utility of T-NGS to clarify the genetic heterogeneity that underlies PrCa predisposition, allowing to detect both small and large genomic variations, and unveil CHEK2 and ATM as the major HRR genes associated with early-onset and familial PrCa, respectively.