Prostate cancer (PCa) has a strong genetic susceptibility, with an estimated heritability rate of 57% [1]. To date, hundreds of common risk-associated genetic variants have been identified from genome-wide association studies [2], [3]. In addition, it has been shown that rare pathogenic mutations in several major genes such as HOXB13, BRCA2, ATM, CHEK2 and PALB2 are associated with higher PCa risk, particularly for more aggressive disease [4], [5], [6], [7], [8]. These genetic variants have important clinical utility in PCa risk stratification for the development of personalized cancer screening strategies [9], [10], [11].

Most of the genes for which an association with PCa susceptibility has been established are involved in DNA repair [5], [6], [7], [8]. Inherited mutations in DNA repair genes reduce the capacity to correct DNA damage, resulting in accumulation of somatic mutations that can lead to cancer. Furthermore, PCa cells with DNA repair deficiency, particularly in the homologous recombination pathway, often exhibit greater reliance on the PARP1-mediated base excision repair pathway, making them highly sensitive to PARP inhibitor (PARPi) therapy owing to the “synthetic lethality” principle [12]. A therapeutic synthetic lethality effect was observed after PARPi therapy among PCa patients whose tumors harbored pathogenic variants of BRCA2 or other DNA repair genes [13]. However, few other genes for which inactivation leads to a synthetic lethality effect similar to BRCA2 have been identified.

Tsujino et al [14] recently identified a novel set of 65 genes for which experimental inactivation via CRISPR - conferred PARPi sensitivity in PCa cell lines. Their findings suggest that inactivation of these genes could influence susceptibility to PCa and create a synthetic lethality effect with potential therapeutic benefits [12]. In the present study, we tested the association of this set of genes with PCa risk, which may predict not only predisposition to PCa development but also sensitivity to PARPi therapy.