title: Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer.
abstract: 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.
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Matthew K H
authors.initials: MK
authors.lastname: Hong
authors.affiliation: 1] Centre for Neural Engineering, Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia [2] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [3] Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Geoff
authors.initials: G
authors.lastname: Macintyre
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium [3] Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Peter
authors.identifier: 0000000302921949
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [2] Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Keval
authors.initials: K
authors.lastname: Patel
authors.affiliation: Centre for Translational Pathology, University of Melbourne, Parkville 3050, Victoria, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.affiliation: 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors.forename: Ludmil B
authors.identifier: 0000000335964515
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville 3050, Victoria, Australia.
authors.forename: Clare
authors.initials: C
authors.lastname: Sloggett
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia [3] Centre for Neural Engineering, Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia [4] Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Marek
authors.initials: M
authors.lastname: Cmero
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marass
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Tsui
authors.affiliation: Centre for Neural Engineering, Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mangiola
authors.affiliation: Victorian Life Sciences Computation Initiative, The University of Melbourne, Parkville 3050, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lonie
authors.affiliation: 1] Centre for Neural Engineering, Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria 3010, Australia [2] Diagnostic Genomics, NICTA, Victoria Research Laboratory, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Haroon
authors.initials: H
authors.lastname: Naeem
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sapre
authors.affiliation: Department of Radiology, Royal Melbourne Hospital, Parkville 3050, Victoria, Australia.
authors.forename: Pramit M
authors.initials: PM
authors.lastname: Phal
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Kurganovs
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Chin
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Michael
authors.identifier: 000000029745728X
authors.initials: M
authors.lastname: Kerger
authors.affiliation: Department of Histopathology, University Cambridge Hospitals, Addenbrookes Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [2] Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK [2] Academic Urology Group, Addenbrookes Hospital, Cambridge University, Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gnanapragasam
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: 1] TissuPath Specialist Pathology, Mount Waverley 3149, Victoria, Australia [2] Monash University Faculty of Medicine, Clayton 3168, Victoria, Australia.
authors.forename: John S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: TissuPath Specialist Pathology, Mount Waverley 3149, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ryan
authors.affiliation: Bar-Ilan University Medical School, Safad 1311502, Israel.
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Costello
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Niall M
authors.initials: NM
authors.lastname: Corcoran
authors.affiliation: 1] Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne, Parkville 3050, Victoria, Australia [2] The Epworth Prostate Centre, Epworth Hospital, Richmond 3121, Victoria, Australia.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hovens
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D056915:DNA Copy Number Variations; D018450:Disease Progression; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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