title: Genomic hallmarks of localized, non-indolent prostate cancer.
abstract: Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Fraser
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Veronica Y
authors.initials: VY
authors.lastname: Sabelnykova
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Takafumi N
authors.initials: TN
authors.lastname: Yamaguchi
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Heisler
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Livingstone
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Huang
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Shiah
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Fouad
authors.initials: F
authors.lastname: Yousif
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Xihui
authors.initials: X
authors.lastname: Lin
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Andre P
authors.initials: AP
authors.lastname: Masella
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Fox
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Xie
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Berlin
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Musaddeque
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Trudel
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Luo
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Beck
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Meng
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Junyan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Alister
authors.initials: A
authors.lastname: D'Costa
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Denroche
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Haiying
authors.initials: H
authors.lastname: Kong
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Shadrielle Melijah G
authors.initials: SM
authors.lastname: Espiritu
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Melvin L K
authors.initials: ML
authors.lastname: Chua
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Ada
authors.initials: A
authors.lastname: Wong
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Taryne
authors.initials: T
authors.lastname: Chong
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sam
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Johns
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Timms
authors.affiliation: Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Buchner
authors.affiliation: Department of Pathology and Research Centre of CHU de Québec-Université Laval. Québec City, Canada.
authors.forename: Michèle
authors.initials: M
authors.lastname: Orain
authors.affiliation: Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Picard
authors.affiliation: Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
authors.forename: Helène
authors.initials: H
authors.lastname: Hovington
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Murison
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Ken
authors.initials: K
authors.lastname: Kron
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Harding
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: P'ng
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Houlahan
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Chu
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Lo
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Nguyen
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Constance H
authors.initials: CH
authors.lastname: Li
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Pharmacology &Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Ren X
authors.initials: RX
authors.lastname: Sun
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: de Borja
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Cooper
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Julia F
authors.initials: JF
authors.lastname: Hopkins
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Shaylan K
authors.initials: SK
authors.lastname: Govind
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Clement
authors.initials: C
authors.lastname: Fung
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Green
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Chan-Seng-Yue
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Jung
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Bergeron
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Dal Pra
authors.affiliation: Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Lacombe
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.|Vancouver Prostate Centre, Vancouver, Canada.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.affiliation: School of Computing Science, Simon Fraser University, Burnaby, Canada.
authors.forename: Cenk
authors.initials: C
authors.lastname: Sahinalp
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.affiliation: Division of Urology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Housheng H
authors.initials: HH
authors.lastname: He
authors.affiliation: Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Fradet
authors.affiliation: Department of Pathology and Research Centre of CHU de Québec-Université Laval. Québec City, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Tetu
authors.affiliation: Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: Informatics &Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Pharmacology &Toxicology, University of Toronto, Toronto, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000072837:Chromothripsis; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D059472:Exome / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000473:pathology; D012008:Recurrence