| Literature DB >> 26005866 |
Paul C Boutros1, Michael Fraser2, Nicholas J Harding3, Richard de Borja3, Dominique Trudel4, Emilie Lalonde5, Alice Meng6, Pablo H Hennings-Yeomans3, Andrew McPherson7, Veronica Y Sabelnykova3, Amin Zia3, Natalie S Fox5, Julie Livingstone3, Yu-Jia Shiah3, Jianxin Wang3, Timothy A Beck3, Cherry L Have4, Taryne Chong3, Michelle Sam3, Jeremy Johns3, Lee Timms3, Nicholas Buchner3, Ada Wong3, John D Watson3, Trent T Simmons3, Christine P'ng3, Gaetano Zafarana2, Francis Nguyen3, Xuemei Luo3, Kenneth C Chu3, Stephenie D Prokopec3, Jenna Sykes8, Alan Dal Pra9, Alejandro Berlin9, Andrew Brown3, Michelle A Chan-Seng-Yue3, Fouad Yousif3, Robert E Denroche3, Lauren C Chong3, Gregory M Chen3, Esther Jung3, Clement Fung3, Maud H W Starmans3, Hanbo Chen3, Shaylan K Govind3, James Hawley3, Alister D'Costa3, Melania Pintilie8, Daryl Waggott3, Faraz Hach7, Philippe Lambin10, Lakshmi B Muthuswamy3, Colin Cooper11, Rosalind Eeles12, David Neal13, Bernard Tetu14, Cenk Sahinalp7, Lincoln D Stein3, Neil Fleshner15, Sohrab P Shah16, Colin C Collins17, Thomas J Hudson3, John D McPherson3, Theodorus van der Kwast4, Robert G Bristow18.
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.Entities:
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Year: 2015 PMID： 26005866 DOI： 10.1038/ng.3315
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330