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      The Evolutionary History of Lethal Metastatic Prostate Cancer

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          Abstract

          Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour 1- 4 . This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths 5 . 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 6- 8 , recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones 9, 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.

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          Most cited references11

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          The clonal evolution of tumor cell populations.

          P C Nowell (1976)
          It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
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            AACR centennial series: the biology of cancer metastasis: historical perspective.

            Metastasis resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His "seed and soil" hypothesis was substantiated a century later with experimental studies, and numerous reports have confirmed these seminal observations. An improved understanding of the metastatic process and the attributes of the cells selected by this process is critical for the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, so metastasis prevention may not be relevant. Treating systemic disease and identifying patients with early disease should be our goal. Revitalized research in the past three decades has focused on new discoveries in the biology of metastasis. Even though our understanding of molecular events that regulate metastasis has improved, the contributions and timing of molecular lesion(s) involved in metastasis pathogenesis remain unclear. Review of the history of pioneering observations and discussion of current controversies should increase understanding of the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and should lead to the design of successful therapy. (c)2010 AACR.
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              Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

              Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                6 March 2015
                01 April 2015
                16 April 2015
                16 October 2015
                : 520
                : 7547
                : 353-357
                Affiliations
                [1 ]Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK
                [2 ]Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium
                [3 ]Cancer Research UK London Research Institute, London, UK
                [4 ]Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich, UK
                [5 ]Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland
                [6 ]The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
                [7 ]Laboratory of Pathology, National Cancer Institute, National Institutes of Health, MD, USA.
                [8 ]University of Liverpool and HCA Pathology Laboratories, London, UK
                [9 ]Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK
                [10 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
                [11 ]Uro-oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK
                [12 ]A list of additional members is provided in the Supplementary Information
                [13 ]Department of Surgical Oncology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK
                [14 ]Royal Marsden NHS Foundation Trust, London and Sutton, UK
                [16 ]Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project
                Author notes

                AUTHOR CONTRIBUTIONS G.G., P.V.L., T.V., D.C.W., U.M. and G.S.B. designed the study and co-wrote the paper. G.G., P.V.L., B.K., L.B.A., J.T., K.J.D., M.A. and D.C.W. carried out bioinformatic analyses. K.K., V.G., C.L. and S.O.’M. carried out laboratory analysis. E.P., D.B., H.C.W., C.C., P.J.C. and all authors edited the paper. D.B., Z.K-J., H.C.W., G.G. and D.C.W. coordinated the study. H.M.L.K. and G.H. performed clinical data analysis and curation. W.I. facilitated the initial development of the autopsy study. M.R.E.-B. provided pathology support. M.N. provided bioinformatics support and supported project development. C.F., D.E., D.E.N., C.C., R.A.E., U.M. and G.S.B. co-designed and co-directed the study and are Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project. The full ICGC Prostate Group created and maintains overall study direction. For this work the primary affiliation of C.S.C. is The Institute of Cancer Research.

                Present Address: Avoneaux Medical Institute, Oxford, MD, USA.

                [* ] Addresses for correspondence: G. Steven Bova, Institute of Biosciences and Medical Technology–BioMediTech, University of Tampere, FI-33014 Tampere, Finland g.steven.bova@ 123456uta.fi ; David C. Wedge, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA United Kingdom dw9@ 123456sanger.ac.uk ; Ultan McDermott, Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA United Kingdom um1@ 123456sanger.ac.uk
                Article
                EMS62345
                10.1038/nature14347
                4413032
                25830880
                95d0cb3a-c086-4630-a64f-6e11b7be8e53
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