DNA 损伤修复 (DDR) 基因中罕见的遗传变异在前列腺癌 (PrCa) 易感性中具有公认的作用。此外，这些基因在治疗上是可靶向的。虽然罕见变异为其他常见癌症的临床管理提供信息，但定义 PrCa 中与罕见疾病相关的变异一直具有挑战性。在这里，对来自两个独立的高风险澳大利亚和北美家族 PrCa 数据集的全基因组和外显子组测序数据进行了询问，以了解新的 DDR 风险变异。罕见的 DDR 基因变异（预计具有破坏性，存在于两个或多个家庭成员中）在 1963 名个体（700 名家族性和 459 名散发性 PrCa 病例、482 名未受影响的亲属和 322 名筛选对照）中被鉴定并随后进行了基因分型，并进行了关联分析进行相关性（MQLS）。在合并数据集中，罕见的 ERCC3 (rs145201970，p = 2.57 × 10-4) 和 BRIP1 (rs4988345，p = 0.025) 变异与 PrCa 风险显着相关。澳大利亚数据集中的 PARP2（rs200603922，p = 0.028）变体和北美数据集中的 MUTYH（rs36053993，p = 0.031）变体也与风险相关。临床病理学特征的评估没有提供变异携带者诊断时年龄较小或疾病级别较高的证据，在未来确定基于基因的靶向治疗的基因筛查资格标准时应考虑到这一点。这项研究为我们对 PrCa 相关 DDR 基因的理解增加了宝贵的知识，这将支持有效的临床筛查和治疗策略。

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10-4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.