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

Year: 2025

Type: article

Abstract: 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 to study relationships 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 the cut-off ≥ 42, was observed more frequently in HRR-mutated vs. 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 BRCA2 or PALB2 genes, as well 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 more significantly associated with aggressive PC features than HRR mutations. The majority of CDK12-mutated tumors demonstrated a distinct type of copy number variations (CNV), i.e., so-called tandem duplication phenotype. Our study suggests that the selection of PC patients for PARPi treatment requires significant revision of existing attitudes towards tumor genetic profiling.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms262411851