新出现的证据表明，转移病变更适合作为疾病谱而不是二元状态来描述。对影响转移性扩散范围和位置的基因组特征的更深入了解可能有助于风险分层和监测。在此，我们确定了原发前列腺癌的基因组变异预测广泛转移潜力。利用cBioPortal从MSK-MET队列中提取了1,312名原发前列腺癌患者的基因组和临床数据。转移部位计数和总生存数据是公开可用的，也被用作主要结局。使用MSK-IMPACT定向测序平台对原发肿瘤样本进行了分析，专注于前列腺癌中经常发生变异的58个基因。Cox比例危险分析确立了不同转移结局患者总死亡危险比（HR）和95％置信区间（CIs）。 在我们的队列中，1,312名患者中有939人（71％）发生了转移，其中113人（8.6％）转移至5个或更多不同的解剖位置（定义为广泛转移，WSM）。骨是最常见的转移部位（36％），80％的具有肝转移的患者有4个或更多的额外转移部位。在转移患者中，转移部位数的增加与死亡风险的增加相关（HR：1.8，95％CI：1.63-1.99，P <0.001）。以下基因的变异在拥有WSM的患者的肿瘤中更为增加：TP53（40％vs. 20％，P <0.0001），FOXA1扩增（8％vs. 3％，P = 0.02），AR扩增（4.4％vs. 1％，P = 0.01），RB1缺失（5.3％vs. 0.7％，P = 0.001）和BRCA2缺失（4.4% vs. 0.7%，P = 0.01）。单变量生存分析显示，所有这些变异都预测了整体生存（P <0.05）。在多元分析中，只有TP53突变和FOXA1和AR扩增是独立的预后因素。FOXA1（n = 37）和AR（n = 13）扩增是互斥的，这些患者的预后非常差（HR：3.57，95％CI：2.26-5.6，P <0.001]。 我们确定了从原发前列腺癌中发现的基因组变异（TP53突变，FOXA1 / AR扩增，RB1 / BRCA2缺失），这些变异预测广泛转移和不良预后。版权所有©2023 Elsevier Inc.，保留所有权利。

Emerging evidence suggests that metastasis is better described as a spectrum of disease rather than a binary state. A greater understanding of the genomic features that determine extent and location of metastatic spread may inform risk stratification and monitoring. Here, we identify genomic alterations from primary prostate carcinomas that are predictive of wide-spread metastatic potential.Genomic and clinical data from 1,312 patients with primary prostate carcinoma were extracted from the MSK-MET cohort through cBioPortal. Metastatic site counts and overall survival (OS) data were publicly available and used as the primary outcomes. Primary tumor samples were profiled using the MSK-IMPACT targeted sequencing platform. We focused on 58 genes frequently altered in prostate cancer. Cox proportional hazard analyses defined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall mortality in patients with different metastatic outcomes.Out of the 1,312 patients in our cohort, 939 (71%) developed metastases, of whom 113 (8.6%) had metastases to 5 or more distinct anatomical sites (defining wide-spread metastases, WSM). Bone was the most common site of metastasis (36%), and 80% of patients with liver metastases had 4 or more additional sites of metastasis. Among patients with metastasis, increasing number of metastatic sites was associated with increased risk of death (HR: 1.8, 95%CI: 1.63-1.99, P < 0.001). Alterations in the following genes were enriched in tumors from patients with WSM vs. others: TP53 (40% vs. 20%, P < 0.0001), FOXA1-amplification (8% vs. 3%, P = 0.02), AR-amplification (4.4% vs. 1%, P = 0.01), RB1-deletion (5.3% vs. 0.7%, P = 0.001), and BRCA2-deletion (4.4% vs. 0.7%, P = 0.01). Univariable survival analysis showed all these alterations were predictive of OS (P < 0.05). On multivariable analysis, only TP53 mutations, and FOXA1 and AR amplifications were independent prognostic factors. FOXA1 (n = 37) and AR (n = 13) amplifications were mutually exclusive and patients with these experienced very poor OS (HR: 3.57, 95%CI:2.26-5.6, P < 0.001].We identified genomic alterations (TP53 mutations, FOXA1/AR amplification, RB1/BRCA2 deletion) from primary prostate carcinomas that are predictive of wide-spread metastases and poor outcome.Copyright © 2023 Elsevier Inc. All rights reserved.