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         headline:Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer
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      headline:Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer
      description:Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood. Primary prostate tumours are known to be genetically heterogeneous and clonal selection has the potential to drive metastasis. Here Hong et al. show that the acquisition of TP53 mutations is linked to clonal expansion and metastatic progression to lethality.
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            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Pramit M. Phal
      affiliation:
            name:Royal Melbourne Hospital
            address:
               name:Department of Radiology, Royal Melbourne Hospital, Parkville, Australia
               type:PostalAddress
            type:Organization
      name:Natalie Kurganovs
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Xiaowen Chin
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Michael Kerger
      url:http://orcid.org/0000-0002-9745-728X
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Anne Y. Warren
      affiliation:
            name:University Cambridge Hospitals, Addenbrookes Hospital
            address:
               name:Department of Histopathology, University Cambridge Hospitals, Addenbrookes Hospital, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:David Neal
      affiliation:
            name:Cancer Research UK Cambridge Institute, University of Cambridge
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust
            address:
               name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Vincent Gnanapragasam
      affiliation:
            name:Cancer Research UK Cambridge Institute, University of Cambridge
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
            name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust
            address:
               name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:Nitzan Rosenfeld
      affiliation:
            name:Cancer Research UK Cambridge Institute, University of Cambridge
            address:
               name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
               type:PostalAddress
            type:Organization
      name:John S. Pedersen
      affiliation:
            name:TissuPath Specialist Pathology
            address:
               name:TissuPath Specialist Pathology, Mount Waverley, Australia
               type:PostalAddress
            type:Organization
            name:Monash University Faculty of Medicine
            address:
               name:Monash University Faculty of Medicine, Clayton, Australia
               type:PostalAddress
            type:Organization
      name:Andrew Ryan
      affiliation:
            name:TissuPath Specialist Pathology
            address:
               name:TissuPath Specialist Pathology, Mount Waverley, Australia
               type:PostalAddress
            type:Organization
      name:Izhak Haviv
      affiliation:
            name:Bar-Ilan University Medical School
            address:
               name:Bar-Ilan University Medical School, Safad, Israel
               type:PostalAddress
            type:Organization
      name:Anthony J. Costello
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Niall M. Corcoran
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      name:Christopher M. Hovens
      affiliation:
            name:Royal Melbourne Hospital and University of Melbourne
            address:
               name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
               type:PostalAddress
            type:Organization
            name:The Epworth Prostate Centre, Epworth Hospital
            address:
               name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Computing and Information Systems, Centre for Neural Engineering, University of Melbourne, Parkville, Australia
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Australia
      name:Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK
      name:Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK
      name:Department of Human Genetics, KU Leuven, Leuven, Belgium
      name:Cancer Research UK London Research Institute, London, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge, UK
      name:Centre for Translational Pathology, University of Melbourne, Parkville, Australia
      name:Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK
      name:Theoretical Division, Los Alamos National Laboratory, Los Alamos, USA
      name:Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Computing and Information Systems, Centre for Neural Engineering, University of Melbourne, Parkville, Australia
      name:Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Australia
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Department of Computing and Information Systems, Centre for Neural Engineering, University of Melbourne, Parkville, Australia
      name:Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville, Australia
      name:Department of Computing and Information Systems, Centre for Neural Engineering, University of Melbourne, Parkville, Australia
      name:Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Radiology, Royal Melbourne Hospital, Parkville, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Histopathology, University Cambridge Hospitals, Addenbrookes Hospital, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge, UK
      name:Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
      name:TissuPath Specialist Pathology, Mount Waverley, Australia
      name:Monash University Faculty of Medicine, Clayton, Australia
      name:TissuPath Specialist Pathology, Mount Waverley, Australia
      name:Bar-Ilan University Medical School, Safad, Israel
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia
      name:Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia
      name:The Epworth Prostate Centre, Epworth Hospital, Richmond, Australia

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