De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

新发转移性前列腺癌具有高度侵袭性，但常规收集组织的缺乏阻碍了基因组分层和精准肿瘤学。在这里，我们利用一项对 43 例新发转移性前列腺癌进行手术干预的罕见研究来评估 607 个同步原发性和转移性组织区域以及循环肿瘤 DNA 的体细胞基因型。前列腺内异质性普遍存在并影响临床相关基因，导致选定的原发限制区域和同步转移之间的基因型不一致。额外的复杂性是由系统发育相关的主要群体的多克隆转移播种驱动的。当依赖于单一组织区域模拟临床实践时，基因组异质性加上样本中不同的肿瘤分数会导致显性疾病的基因分型不准确；然而，在测序之前汇集从多个活检核心提取的 DNA 可以挽救错误分配的体细胞基因型。我们的结果定义了患有新发转移性前列腺癌的男性中同步治疗敏感的原发性和转移性病变之间的关系，并为实施基因组学指导的患者管理提供了框架。