Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles.
Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington.
JAMA Oncol. 2023 Nov 1;9(11):1514-1524. doi: 10.1001/jamaoncol.2023.3482.
IMPORTANCE: 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. OBJECTIVE: To identify genes associated with aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURE: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.
重要性：对于患有晚期前列腺癌（PCa）或有癌症家族史的男性，建议进行种系基因面板检测。虽然目前纳入面板检测的一些基因的证据有限，但基因面板也可能不完整，并且会遗漏影响 PCa 风险和侵袭性疾病的基因。 目的：确定与侵袭性 PCa 相关的基因。 设计、地点和参与者：这是一项两阶段外显子组测序病例对照遗传关联研究，包括来自 18 项国际研究的 18,945 名欧洲血统男性参与者。数据分析于 2021 年 1 月至 2023 年 3 月进行。参与者包括 9185 名患有侵袭性 PCa（包括 6033 名死于 PCa 和 2397 名经证实转移）和 8361 名非侵袭性 PCa 男性。 暴露情况：对测序数据进行了全外显子组评估，并对 29 个 DNA 修复途径和癌症易感性基因进行了重点研究，其中许多基因都包含在基因面板中。 主要结果和措施：主要研究结果是侵袭性（类别 T4 或 T3 和 Gleason 评分≥8 肿瘤，转移性 PCa 或 PCa 死亡）与非侵袭性 PCa（类别 T1 或 T2 和 Gleason 评分≤6 肿瘤，无已知复发）和转移性与非侵袭性 PCa。 结果：共纳入 17546 名欧洲血统男性进行分析；侵袭性 PCa 患者的诊断时平均（SD）年龄为 65.1（9.2）岁，非侵袭性疾病患者为 63.7（8.0）岁。与侵袭性或转移性 PCa 最强的关联证据是已知 PCa 风险基因 BRCA2 和 ATM 中的罕见有害变异（P≤1.9×10-6），其次是 NBN（P=1.7×10-4）。本研究发现 MSH2、XRCC2 和 MRE11A 中的罕见有害变异有名义证据（P<0.05）。另外 5 个基因的风险（OR≥2）有证据，但侵袭性和非侵袭性 PCa 之间的携带者频率差异无统计学意义：TP53、RAD51D、BARD1、GEN1 和 SLX4。11 个候选基因中的有害变异在 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 患者中携带。 结论和相关性：这项研究的结果进一步支持 DNA 修复和癌症易感性基因，以更好地为 PCa 男性提供疾病管理信息，并将检测扩展到非侵袭性疾病的男性，因为携带这些基因中的有害等位基因的男性更有可能发展为更晚期的疾病。
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