The evolutionary history of lethal metastatic prostate cancer

摘要

Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. 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 supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here 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 characterized 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 denovo 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.%Gunes Gundem等人对人类前列腺肿瘤和它们的转移瘤的亚克隆组成进行了分析,从而确定了这些癌症的形成和扩散背后的演变史。重要的是,他们发现,转移瘤有可能被"补种"多次,从一个转移点向另一个转移点的扩散经常发生。这项研究为在肿瘤内以及原发性肿瘤和转移瘤之间存在的遗传改变和表观遗传改变的巨大多样性的根源提供了新线索,也显示了用定向药物进行癌症治疗在临床上所面临的挑战。