title: Spatial genomic heterogeneity within localized, multifocal prostate cancer.
abstract: Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.
authors.affiliation: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Paul C
authors.identifier: 0000000305537520
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Harding
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Richard
authors.identifier: 0000000281816348
authors.initials: R
authors.lastname: de Borja
authors.affiliation: Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Trudel
authors.affiliation: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Pablo H
authors.initials: PH
authors.lastname: Hennings-Yeomans
authors.affiliation: School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Andrew
authors.identifier: 0000000256545101
authors.initials: A
authors.lastname: McPherson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Veronica Y
authors.initials: VY
authors.lastname: Sabelnykova
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Amin
authors.initials: A
authors.lastname: Zia
authors.affiliation: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Fox
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Livingstone
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Shiah
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Beck
authors.affiliation: Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Cherry L
authors.initials: CL
authors.lastname: Have
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Taryne
authors.initials: T
authors.lastname: Chong
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sam
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Johns
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Timms
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Buchner
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Ada
authors.initials: A
authors.lastname: Wong
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Watson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Trent T
authors.initials: TT
authors.lastname: Simmons
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: P'ng
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Nguyen
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Luo
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Chu
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Dal Pra
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Berlin
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brown
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Chan-Seng-Yue
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Fouad
authors.initials: F
authors.lastname: Yousif
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Denroche
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Chong
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Chen
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Jung
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Clement
authors.initials: C
authors.lastname: Fung
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Maud H W
authors.initials: MH
authors.lastname: Starmans
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Hanbo
authors.initials: H
authors.lastname: Chen
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Shaylan K
authors.initials: SK
authors.lastname: Govind
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Hawley
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Alister
authors.initials: A
authors.lastname: D'Costa
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Faraz
authors.initials: F
authors.lastname: Hach
authors.affiliation: Department of Radiotherapy, Maastricht University, Maastricht, the Netherlands.
authors.forename: Philippe
authors.identifier: 0000000290340177
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Muthuswamy
authors.affiliation: 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK. [2] Department of Biological Sciences, University of East Anglia, Norwich, UK. [3] School of Medicine, University of East Anglia, Norwich, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Cooper
authors.affiliation: 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK. [2] Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: 1] Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK. [2] Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.affiliation: Department of Pathology, Laval University, Quebec City, Quebec, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Tetu
authors.affiliation: School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Cenk
authors.initials: C
authors.lastname: Sahinalp
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.affiliation: Division of Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: Fleshner
authors.affiliation: 1] Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada. [3] British Columbia Cancer Agency Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: 1] Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. [2] Laboratory for Advanced Genome Analysis, Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Thomas J
authors.identifier: 0000000213764849
authors.initials: TJ
authors.lastname: Hudson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.affiliation: Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [2] Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [3] Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics
chemical_list: C000596782:MYCL protein, human; D016271:Proto-Oncogene Proteins c-myc