Complex Relationships Between Homologous Recombination Deficiency (HRD) Score and Mutational Status of Homologous Recombination Repair (HRR) Genes in Prostate Carcinomas

Homologous recombination deficiency (HRD) resulting from inactivation of BRCA1/2 genes promotes chromosomal instability and renders tumor cells susceptible to platinum derivatives and PARP inhibitors (PARPi). The contribution of alterations in other homologous recombination repair (HRR) genes to HRD remains understudied. This investigation aimed to analyze the spectrum of mutations in 34 HRR genes in prostate carcinomas (PCs) and study the relationship between HRR status and HRD. HRR mutations and HRD scores were examined by NGS in 1131 and 680 PCs, respectively. Pathogenic or likely pathogenic variants in HRR genes were detected in 216/1131 cases (19.1%). HRD, defined by an HRD score cut-off of ≥42, was observed more frequently in HRR-mutated than in wild-type tumors (23/120 (19.2%) vs. 29/560 (5.2%), p < 0.0001). The highest HRD scores were detected in PCs with biallelic inactivation of the BRCA2 or PALB2 genes, as well as in tumors with BRIP1 mutations. HRD was also occasionally seen in PCs with ATM, NBN, FANCM, BRCA1 and CDK12 alterations, but never in cases with CHEK2 mutations. HRD was significantly more associated with aggressive PC features than HRR mutations. The majority of CDK12-mutated tumors exhibited a distinct type of copy number variations (CNV)–a tandem duplication phenotype. Our study suggests that the selection of PC patients for PARPi treatment requires a significant revision of existing attitudes towards tumor genetic profiling.