Genome Sequencing Reveals Metastatic Seeding Patterns in Prostate Cancer

Metastasis is the leading cause of cancer-related deaths; yet, little is known about the mechanisms that govern cancer cell spread. Recent work in murine cancer models suggests that polyclonal seeding and cooperative intratumor heterogeneity may serve as drivers of metastatic progression, prompting Gundem and colleagues to characterize clonal relationships in metastatic androgen-deprived prostate cancer. Whole-genome sequencing of 51 tumors from 10 patients revealed that, in 50% of cases, clusters of mutations occurred at subclonal proportions and were detected across multiple metastatic samples, suggesting that polyclonal seeding between different distant sites is a common mechanism of metastasis in prostate cancer. Importantly, patients with polyclonal metastases harbored distinct subclonal alterations that have been associated with androgen-deprivation therapy (ADT) resistance and bypass of the androgen receptor (AR) pathway, including alterations in AR or genes downstream of AR or via AR-independent mechanisms, such as MYC amplification and CTNNB1 mutation. Phylogenetic mapping of the order of acquisition of mutations across multiple metastases within a single patient revealed two different patterns of metastatic spread: linear spread, in which specific subclones subsequently seeded all metastases, and branching spread, in which a complex pattern of polyclonal seeding occurred between multiple metastatic sites. Interestingly, truncal mutations shared between the primary tumor and all metastases highlighted driver events, including loss of the tumor suppressors TP53, PTEN, RB1, and CDKN1B early in tumor evolution. In contrast, genetic alterations in AR signaling components that drive castration resistance occurred post–metastatic spread, with convergent evolution across metastatic samples, suggesting that tumor cells are under constant selective pressure to bypass AR throughout metastatic progression. Together, this work defines the evolutionary genetic landscape of androgen-deprived metastatic prostate cancer and supports the idea that spread between distant sites promotes metastasis and drives resistance to ADT via clonal diversification.

Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JM, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature Apr 1 [Epub ahead of print].