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Nat Genet. 2015 Jul;47(7):736-45. doi: 10.1038/ng.3315. Epub 2015 May 25.

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

Author information

1
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.
2
Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
3
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
4
Department of Pathology and Laboratory Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
5
1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
6
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
7
School of Computing Science, Simon Fraser University, Burnaby, British Columbia, Canada.
8
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
9
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
10
Department of Radiotherapy, Maastricht University, Maastricht, the Netherlands.
11
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.
12
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.
13
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.
14
Department of Pathology, Laval University, Quebec City, Quebec, Canada.
15
Division of Urology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
16
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.
17
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.
18
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.

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.

PMID:
26005866
DOI:
10.1038/ng.3315
[Indexed for MEDLINE]

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