bstract 956: The evolutionary history of lethal metastatic prostate cancer
Gundem G., Van Loo P., Kremeyer B., Alexandrov LB., Tubio JMC., Papaemmanuil E., Brewer DS., Kallio H., Högnäs G., Annala M., Kivinummi K., Goody V., Latimer C., O'Meara S., Dawson KJ., Isaacs W., Emmert-Buck MR., Nykter M., Foster C., Kote-Jarai Z., Easton D., Whitaker HC., Neal DE., Cooper CS., Eeles RA., Visakorpi T., Campbell PJ., McDermott U., Wedge DC., Bova GS.
Abstract Cancers emerge from an on-going 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 inter-clonal cooperation between multiple subclones. 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. Citation Format: Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B. Alexandrov, Jose M.C. Tubio, Elli Papaemmanuil, Daniel S. Brewer, Heini Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J. Dawson, William Isaacs, Michael R. Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C. Whitaker, David E. Neal, Colin S. Cooper, Rosalind A. Eeles, Tapio Visakorpi, Peter J. Campbell, Ultan McDermott, David C. Wedge, G. S. Bova. The evolutionary history of lethal metastatic prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2015-956