The evolutionary history of lethal metastatic prostate cancer

Abstract

Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour1-4. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths5. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported6-8, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones9,10. In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.

New Perspectives in Medical Oncology : Molecular Medicine and its Perspectives

“…La plupart des maladies néoplasiques fréquentes se voient ainsi démembrées en de multiples entités moléculaires de pronostic différent, et requérant des traitements potentiellement différents (1)(2)(3)(4)(5)(6). La gestion clinique de cette complexité reste à ce stade largement empirique, guidée par les essais cliniques « basket » et « umbrella », « paniers » et « parapluie » actuellement en cours de réalisation et décrits dans ce document.…”

Cancer evolution and heterogeneity

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…• AR signaling-driven castration resistance can be acquired via multiple and convergent events in different metastases, a phenomenon explained by the selective pressure of ADT (Gundem et al 2015). What are the therapeutic consequences of the co-existence of multiple forms of persistent, aberrant AR signaling in (Mestayer et al 2003, Xu et al 2009a).…”