Spatial genomic heterogeneity within localized, multifocal prostate cancer

Paul C Boutros; Michael Fraser; Nicholas J Harding; Richard de Borja; Dominique Trudel; Emilie Lalonde; Alice Meng; Pablo H Hennings-Yeomans; Andrew McPherson; Veronica Y Sabelnykova; Amin Zia; Natalie S Fox; Julie Livingstone; Yu-Jia Shiah; Jianxin Wang; Timothy A Beck; Cherry L Have; Taryne Chong; Michelle Sam; Jeremy Johns; Lee Timms; Nicholas Buchner; Ada Wong; John D Watson; Trent T Simmons; Christine P'ng; Gaetano Zafarana; Francis Nguyen; Xuemei Luo; Kenneth C Chu; Stephenie D Prokopec; Jenna Sykes; Alan Dal Pra; Alejandro Berlin; Andrew Brown; Michelle A Chan-Seng-Yue; Fouad Yousif; Robert E Denroche; Lauren C Chong; Gregory M Chen; Esther Jung; Clement Fung; Maud H W Starmans; Hanbo Chen; Shaylan K Govind; James Hawley; Alister D'Costa; Melania Pintilie; Daryl Waggott; Faraz Hach; Philippe Lambin; Lakshmi B Muthuswamy; Colin Cooper; Rosalind Eeles; David Neal; Bernard Tetu; Cenk Sahinalp; Lincoln D Stein; Neil Fleshner; Sohrab P Shah; Colin C Collins; Thomas J Hudson; John D McPherson; Theodorus van der Kwast; Robert G Bristow

doi:10.1038/ng.3315

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Spatial genomic heterogeneity within localized, multifocal prostate cancer

Journal article

Peer reviewed

Spatial genomic heterogeneity within localized, multifocal prostate cancer

Paul C Boutros, Michael Fraser, Nicholas J Harding, Richard de Borja, Dominique Trudel, Emilie Lalonde, Alice Meng, Pablo H Hennings-Yeomans, Andrew McPherson, Veronica Y Sabelnykova, …

Nature genetics, Vol.47(7), pp.736-+

2015-07

DOI: https://doi.org/10.1038/ng.3315

PMID: 26005866

Abstract

Prostatic Neoplasms - pathology

Genetic Association Studies

Humans

Middle Aged

Male

Genetic Heterogeneity

DNA Copy Number Variations

Point Mutation

Neoplasm Grading

Prostatic Neoplasms - genetics

Cell Line, Tumor

Polymorphism, Single Nucleotide

Proto-Oncogene Proteins c-myc - genetics

Genome, Human

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.147 Prostate Cancer; 1.147.859 Androgen Receptor
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Spatial genomic heterogeneity within localized, multifocal prostate cancer
Creators: Paul C Boutros - 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
Michael Fraser - Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Nicholas J Harding - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Richard de Borja - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Dominique Trudel - Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Emilie Lalonde - 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Alice Meng - Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
Pablo H Hennings-Yeomans - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Andrew McPherson - School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada
Veronica Y Sabelnykova - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Amin Zia - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Natalie S Fox - 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Julie Livingstone - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Yu-Jia Shiah - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Jianxin Wang - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Timothy A Beck - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Cherry L Have - Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Taryne Chong - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Michelle Sam - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Jeremy Johns - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Lee Timms - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Nicholas Buchner - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Ada Wong - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
John D Watson - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Trent T Simmons - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Christine P'ng - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Gaetano Zafarana - Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Francis Nguyen - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Xuemei Luo - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Kenneth C Chu - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Stephenie D Prokopec - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Jenna Sykes - Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Alan Dal Pra - Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
Alejandro Berlin - Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
Andrew Brown - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Michelle A Chan-Seng-Yue - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Fouad Yousif - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Robert E Denroche - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Lauren C Chong - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Gregory M Chen - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Esther Jung - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Clement Fung - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Maud H W Starmans - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Hanbo Chen - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Shaylan K Govind - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
James Hawley - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Alister D'Costa - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Melania Pintilie - Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Daryl Waggott - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Faraz Hach - School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada
Philippe Lambin - Department of Radiotherapy, Maastricht University, Maastricht, the Netherlands
Lakshmi B Muthuswamy - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Colin Cooper - 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK. Department of Biological Sciences, University of East Anglia, Norwich, UK. School of Medicine, University of East Anglia, Norwich, UK
Rosalind Eeles - 1] Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK. Royal Marsden National Health Service (NHS) Foundation Trust, London and Sutton, UK
David Neal - 1] Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK. Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
Bernard Tetu - Department of Pathology, Laval University, Quebec City, Quebec, Canada
Cenk Sahinalp - School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada
Lincoln D Stein - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Neil Fleshner - Division of Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Sohrab P Shah - 1] Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada. Department of Computer Science, University of British Columbia, Vancouver, British Columbia, Canada. British Columbia Cancer Agency Research Centre, Vancouver, British Columbia, Canada
Colin C Collins - 1] Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Laboratory for Advanced Genome Analysis, Vancouver Prostate Centre, Vancouver, British Columbia, Canada
Thomas J Hudson - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
John D McPherson - Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Theodorus van der Kwast - Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
Robert G Bristow - 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
Publication Details: Nature genetics, Vol.47(7), pp.736-+
Grant note: Canadian Institutes of Health Research
Academic Unit: Miller School of Medicine; UMMG Department of Neurology; UMMG Dept of Radiation Oncology
Language: English
Resource Type: Journal article
PMID: 26005866
Record Identifier: 991031598280502976