[Homologous recombination repair gene variants in hormone-sensitive prostate cancer]

Objective: To investigate the characteristics of germline/somatic homologous recombination repair (HRR) gene variants in patients with hormone-sensitive prostate cancer (HSPC) and to analyze their associations with clinicopathological features. Methods: A retrospective study was conducted on 108 clinicopathologically high-risk HSPC patients diagnosed at the Peking University Third Hospital, Beijing, China from 2019 to 2022. Next generation sequencing (NGS) was used to simultaneously detect germline and somatic gene variants (32-98 genes, including at least 19 HRR-related genes). The HRR gene variation profiles were characterized. Their correlations with clinicopathological characteristics were analyzed. Results: Genetic mutations were found in 23 patients, the age ranged from 36 to 83, with an age of 66(56,68)years. Germline HRR gene variants were detected in 4 (3.7%, 4/108) of the 108 patients, with BRCA2 being most common (1.9%, 2/108), followed by PALB2(0.9%)/RAD51D(0.9%). Somatic HRR gene variants were identified in 14 patients (13.0%, 14/108), involving 17 variants (affecting BRCA1/BRCA2/ATM/CDK12/FANCA). CDK12 was the most frequently mutated gene. Among these 14 patients, 3 had two different variants (either in different genes or two distinct variants in the same gene). In addition to the most common point-mutations and small insertions/deletions, copy number loss of BRCA1 was detected in 1 case. Non-HRR-related gene variants were identified in 5 patients. Among them, 3(2.8%) had TP53 variants (1 case had mixed acinar and ductal adenocarcinoma) and 2 had PTEN and KRAS mutations. Compared with the patients without gene variations, the ones with somatic HRR gene variations were younger, presented with higher serum total prostate-specific antigen (PSA) levels and more advanced tumor stage (all P<0.05). No significant correlations were observed between somatic HRR gene variants and free PSA levels or grade groups (P>0.05). Conclusions: HSPC exhibits high genetic heterogeneity. BRCA2 is the most common gene with germline variations, while CDK12 is the most frequently mutated gene in somatic HRR variants. This study suggests that HRR gene testing in patients with high-risk HSPC would help identify those with more aggressive clinical features and guide prognostication and potential targeted therapeutic strategies.