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, Nature genetics 47, 736-45 (2015) 2015
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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.