建议对患有晚期前列腺癌（PCa）或有家族癌症史的男性进行生殖系基因检测。虽然目前包括在基因检测中的一些基因的证据有限，但基因检测也很可能是不完全的，缺少影响PCa风险和侵袭性疾病的基因。为了鉴定与侵袭性PCa相关的基因，进行了一个2阶段外显子测序单一病例遗传关联研究，包括来自18个国际研究的欧洲血统男性。数据分析从2021年1月到2023年3月进行。参与者包括9185名患有侵袭性PCa的男性（其中6033人死于PCa，2397人确认有转移）和8361名患有非侵袭性PCa的男性。 我们对全外显子组测序数据进行了评估，并对包括在基因检测中的29个DNA修复途径和癌症易感基因进行了重点研究。主要研究结果是侵袭性（T4类别或T3和格里森评分≥8的肿瘤，有转移的PCa或PCa死亡）与非侵袭性PCa（T1或T2类别和格里森评分≤6的肿瘤，无已知复发）以及转移性与非侵袭性PCa之间的差异。 分析纳入了17546名欧洲血统男性；侵袭性PCa患者的平均（标准差）诊断年龄为65.1（9.2）岁，非侵袭性疾病患者为63.7（8.0）岁。侵袭性或转移性PCa与已知PCa风险基因BRCA2和ATM中罕见的有害变异相关性最强（P≤1.9×10-6），其次是NBN（P=1.7×10-4）。本研究发现了与MSH2、XRCC2和MRE11A中罕见的有害变异相关的名义证据（P<0.05）。另外五个基因存在更高风险的证据（OR≥2），但侵袭性和非侵袭性PCa患者之间的携带频率差异在统计学上没有显著性：TP53、RAD51D、BARD1、GEN1和SLX4。这些11个候选基因中的有害变异存在于2.3%的非侵袭性PCa患者、5.6%的侵袭性PCa患者和7.0%的转移性PCa患者中。 本研究的结果进一步支持了DNA修复和癌症易感基因在指导PCa患者的疾病管理方面的作用，并建议将检测范围扩展到非侵袭性疾病的男性，因为携带这些基因的有害等位基因的男性很可能发展为更严重的疾病。

Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease.To identify genes associated with aggressive PCa.A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa.Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels.The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa.A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa.The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.