University College London Cancer Institute, London, UK.
University College London Hospitals, London, UK.
Nat Commun. 2023 Aug 10;14(1):4823. doi: 10.1038/s41467-023-40315-9.
Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10 and 6.4 × 10). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.
尽管最初对激素治疗有反应，但转移性前列腺癌总是会发展为致命状态。为了描述逃避治疗的转移性肿瘤的患者内进化关系，我们对 10 名死于前列腺癌的男性死后从 11 个器官中采集的 167 个转移性区域进行了全基因组拷贝数分析，并针对雄激素受体 (AR) 进行了定制方法。我们在每个患者的转移灶中都发现了围绕 AR 的不同且患者特有的改变，这些改变表明在个体中独立获得了相关的基因组变化，并且在一些患者中，AR 中性克隆同时存在。使用泛着丝粒拷贝数变化的基因组边界，我们确认了转移灶和诊断性活检之间存在共同的克隆起源，并在个别患者中，确定了由具有不同常染色体拷贝数改变的优势克隆占据的转移灶簇。这些由染色体定义的簇的特征是簇特异性的 AR 基因结构，在两个指数病例中，拓扑结构比随机更一致（p 值分别为 3.07×10 和 6.4×10）。与解剖部位的整合表明了传播模式和基因组分歧点。在这里，我们表明，拷贝数边界可以识别出具有潜在不同致死轨迹的治疗选择克隆。
