转录为Chingshua证明变化的DNA损伤反应（DDR）基因在转移性去势抵抗性前列腺癌（mCRPC）中很常见。了解这些基因组事件如何影响预后和/或治疗反应对于优化临床结果至关重要。对来自375名mCRPC患者的407个血浆样本进行了定向测序。使用CLIA认证的PredicineCARE™无细胞DNA（cfDNA）分析，评估了152个关键基因（包括27个DDR相关基因）中的致病性变化以及BRCA2的双等位基因丧失的存在和机制。至少有一个DDR变异在34.5％（129/375）的患者中存在（包括单等位点突变）。最常见的DDR基因突变是BRCA2（19％），ATM（13％），FANCA（5％），CHEK2（5％）和BRCA1（3％）。存在BRCA变异的患者，尤其是BRCA2，其无进展生存期（Hazard ratio (HR) 3.3 [95％ CI 1.9-6.0]；回归p < 0.001），总生存期（HR 2.2 [95％ CI 1.1-4.5]；回归p = 0.02）和雄激素受体（AR）通路抑制剂的PSA反应率（32％vs 60％，卡方p = 0.02）明显较差。BRCA缺陷肿瘤中也富集了多个基因的变异，包括AR和PI3K通路。BRCA2变异的杂合性对临床结果没有明显影响，单等位丧失和双等位丧失的无进展生存期均较差（中位数3.9个月vs 3.4个月vs拷贝中性9.8个月）。这些数据强调了BRCA基因，尤其是BRCA2，在mCRPC中的关键预后生物标志物。BRCA2作为不良预后的标志物的临床效用可能独立于检测到的杂合状态，在cfDNA测序中可能是如此。来自BRCA缺陷mCRPC的cfDNA中可操作的基因组变异的富集可能支持未来临床试验中的合理共靶策略。本研究获得了几个资金来源的支持，详细列表请参见致谢部分。在进行该研究期间未收到Predicine, Inc.的资助。版权所有 © 2023 Elsevier B.V. 发表。

Genomic alterations in DNA damage response (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC). Understanding how these genomic events impact prognosis and/or treatment response is vital for optimising clinical outcomes.Targeted sequencing was performed on 407 plasma samples from 375 men with mCRPC. Using the CLIA-certified PredicineCARE™ cell-free DNA (cfDNA) assay, pathogenic alterations in 152 key genes (including 27 DDR-related genes) were assessed, as was the presence and mechanisms of biallelic loss in BRCA2.At least one DDR alteration was present in 34.5% (129/375) of patients (including monoallelic alterations). The most frequently altered DDR genes were BRCA2 (19%), ATM (13%), FANCA (5%), CHEK2 (5%) and BRCA1 (3%). Patients with BRCA alterations, especially BRCA2, had significantly worse progression-free survival (PFS) (Hazard ratio (HR) 3.3 [95% CI 1.9-6.0]; Cox regression p < 0.001), overall survival (HR 2.2 [95% CI 1.1-4.5]; Cox regression p = 0.02) and PSA response rates to androgen receptor (AR) pathway inhibitors (32% vs 60%, chi-square p = 0.02). BRCA-deficient tumours were also enriched for alterations within multiple genes including in the AR and PI3K pathways. Zygosity of BRCA2 alterations had no discernible impact on clinical outcomes, with similarly poor PFS for monoallelic vs biallelic loss (median 3.9 months vs 3.4 months vs copy neutral 9.8 months).These data emphasise that the BRCA genes, in particular BRCA2, are key prognostic biomarkers in mCRPC. The clinical utility of BRCA2 as a marker of poor outcomes may, at least in cfDNA assays, be independent of the zygosity state detected. Enrichment of actionable genomic alterations in cfDNA from BRCA-deficient mCRPC may support rational co-targeting strategies in future clinical trials.Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.Copyright © 2023. Published by Elsevier B.V.