Divergent Clonal Evolution and Early Dissemination Promote Genetic Heterogeneity of Metastases in Castration Resistant Prostate Cancer

Lethal prostate cancer (PCa) has passed through at least two evolutionary bottlenecks: acquisition of metastatic potential and development of castration resistance. A better understanding of how this impacts genetic heterogeneity across metastatic sites is needed to develop strategies to block metastatic spread and overcome resistance. By leveraging deep whole-exome sequencing of 93 tumors from 26 patients, we examined patterns of metastatic dissemination and clonal evolution of PCa. Phylogenetic reconstruction and mathematical modeling enabled quantification of the number of mutations and clones in the cancer ecosystem and characterization of each patient's disease as an evolutionary process. While mutations of the earliest pathogenic genetic drivers of PCa were truncal, most other likely passenger mutations, copy-number alterations, and clones arose after the cancer had spread and were confined to individual metastatic sites due to polyclonal and polyphyletic seeding. Single-tissue sequencing tended to overestimate mutation clonality and, apart from truncal drivers, underestimate mutation rates for both individual patients and cohorts. This study highlights the independent evolution of metastatic lesions, which has implications for diagnostic and targeted therapy strategies.