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Genomic hallmarks of localized, non-indolent prostate cancer

Author

Listed:
  • Michael Fraser

    (Princess Margaret Cancer Centre, University Health Network)

  • Veronica Y. Sabelnykova

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Takafumi N. Yamaguchi

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Lawrence E. Heisler

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Julie Livingstone

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Vincent Huang

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Yu-Jia Shiah

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Fouad Yousif

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Xihui Lin

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Andre P. Masella

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Natalie S. Fox

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Michael Xie

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Stephenie D. Prokopec

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Alejandro Berlin

    (University of Toronto)

  • Emilie Lalonde

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Musaddeque Ahmed

    (Princess Margaret Cancer Centre, University Health Network)

  • Dominique Trudel

    (Toronto General Hospital/University Health Network
    †Present Addresses: Department of Pathology and Cancer Axis, Centre Hospitalier de l’Université de Montréal, Montréal, Canada (D.T.); Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 4, CH-3010 Bern, Switzerland. (A.D.P.).)

  • Xuemei Luo

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Timothy A. Beck

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Alice Meng

    (Princess Margaret Cancer Centre, University Health Network)

  • Junyan Zhang

    (Princess Margaret Cancer Centre, University Health Network)

  • Alister D’Costa

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Robert E. Denroche

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Haiying Kong

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Shadrielle Melijah G. Espiritu

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Melvin L. K. Chua

    (University of Toronto)

  • Ada Wong

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Taryne Chong

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Michelle Sam

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Jeremy Johns

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Lee Timms

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Nicholas B. Buchner

    (Genome Technologies Program, Ontario Institute for Cancer Research)

  • Michèle Orain

    (Department of Pathology and Research Centre of CHU de Québec-Université Laval)

  • Valérie Picard

    (Division of Urology and Research Centre of CHU de Québec-Université Laval)

  • Helène Hovington

    (Division of Urology and Research Centre of CHU de Québec-Université Laval)

  • Alexander Murison

    (Princess Margaret Cancer Centre, University Health Network)

  • Ken Kron

    (Princess Margaret Cancer Centre, University Health Network)

  • Nicholas J. Harding

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Christine P’ng

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Kathleen E. Houlahan

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Kenneth C. Chu

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Bryan Lo

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Francis Nguyen

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Constance H. Li

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Ren X. Sun

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Richard de Borja

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Christopher I. Cooper

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Julia F. Hopkins

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Shaylan K. Govind

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Clement Fung

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Daryl Waggott

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Jeffrey Green

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Syed Haider

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Michelle A. Chan-Seng-Yue

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Esther Jung

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Zhiyuan Wang

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research)

  • Alain Bergeron

    (Division of Urology and Research Centre of CHU de Québec-Université Laval)

  • Alan Dal Pra

    (University of Toronto
    †Present Addresses: Department of Pathology and Cancer Axis, Centre Hospitalier de l’Université de Montréal, Montréal, Canada (D.T.); Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 4, CH-3010 Bern, Switzerland. (A.D.P.).)

  • Louis Lacombe

    (Division of Urology and Research Centre of CHU de Québec-Université Laval)

  • Colin C. Collins

    (University of British Columbia
    Vancouver Prostate Centre)

  • Cenk Sahinalp

    (School of Computing Science, Simon Fraser University)

  • Mathieu Lupien

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto)

  • Neil E. Fleshner

    (Princess Margaret Cancer Centre/University Health Network)

  • Housheng H. He

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto)

  • Yves Fradet

    (Division of Urology and Research Centre of CHU de Québec-Université Laval)

  • Bernard Tetu

    (Department of Pathology and Research Centre of CHU de Québec-Université Laval)

  • Theodorus van der Kwast

    (Toronto General Hospital/University Health Network)

  • John D. McPherson

    (University of Toronto
    Genome Technologies Program, Ontario Institute for Cancer Research)

  • Robert G. Bristow

    (Princess Margaret Cancer Centre, University Health Network
    University of Toronto
    University of Toronto)

  • Paul C. Boutros

    (Informatics & Biocomputing Program, Ontario Institute for Cancer Research
    University of Toronto
    University of Toronto)

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.

Suggested Citation

  • Michael Fraser & Veronica Y. Sabelnykova & Takafumi N. Yamaguchi & Lawrence E. Heisler & Julie Livingstone & Vincent Huang & Yu-Jia Shiah & Fouad Yousif & Xihui Lin & Andre P. Masella & Natalie S. Fox, 2017. "Genomic hallmarks of localized, non-indolent prostate cancer," Nature, Nature, vol. 541(7637), pages 359-364, January.
    • Handle: RePEc:nat:nature:v:541:y:2017:i:7637:d:10.1038_nature20788
    DOI: 10.1038/nature20788
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    Citations

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    Cited by:

    1. Michael Fraser & Julie Livingstone & Jeffrey L. Wrana & Antonio Finelli & Housheng Hansen He & Theodorus van der Kwast & Alexandre R. Zlotta & Robert G. Bristow & Paul C. Boutros, 2021. "Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Sujun Chen & Jessica Petricca & Wenbin Ye & Jiansheng Guan & Yong Zeng & Nicholas Cheng & Linsey Gong & Shu Yi Shen & Junjie T. Hua & Megan Crumbaker & Michael Fraser & Stanley Liu & Scott V. Bratman , 2022. "The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yiqun Zhang & Fengju Chen & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2022. "Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Julie Livingstone & Yu-Jia Shiah & Takafumi N. Yamaguchi & Lawrence E. Heisler & Vincent Huang & Robert Lesurf & Tsumugi Gebo & Benjamin Carlin & Stefan Eng & Erik Drysdale & Jeffrey Green & Theodorus, 2021. "The telomere length landscape of prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    5. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Alexander Martinez-Fundichely & Austin Dixon & Ekta Khurana, 2022. "Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Jeroen Kneppers & Tesa M. Severson & Joseph C. Siefert & Pieter Schol & Stacey E. P. Joosten & Ivan Pak Lok Yu & Chia-Chi Flora Huang & Tunç Morova & Umut Berkay Altıntaş & Claudia Giambartolomei & Ji, 2022. "Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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