Spatial genomic heterogeneity within localized, multifocal prostate cancer

Boutros, Paul C, Fraser, Michael, Harding, Nicholas J, De Borja, Richard, Trudel, Dominique, Lalonde, Emilie, Meng, Alice, Hennings-Yeomans, Pablo H, McPherson, Andrew, Sabelnykova, Veronica Y, Zia, Amin, Fox, Natalie S, Livingstone, Julie, Shiah, Yu-jia, Wang, Jianxin, Beck, Timothy A, Have, Cherry L, Chong, Taryne, Sam, Michelle, Johns, Jeremy, Timms, Lee, Buchner, Nicholas, Wong, Ada, Watson, John D, Simmons, Trent T, P'ng, Christine, Zafarana, Gaetano, Nguyen, Francis, Luo, Xuemei, Chu, Kenneth C, Prokopec, Stephenie D, Sykes, Jenna, Dal Pra, Alan, Berlin, Alejandro, Brown, Andrew, Chan-seng-yue, Michelle A, Yousif, Fouad, Denroche, Robert E, Chong, Lauren C, Chen, Gregory M, Jung, Esther, Fung, Clement, Starmans, Maud H W, Chen, Hanbo, Govind, Shaylan K, Hawley, James, D'Costa, Alister, Pintilie, Melania, Waggott, Daryl, Hach, Faraz, Lambin, Philippe, Muthuswamy, Lakshmi B, Cooper, Colin, Eeles, Rosalind, Neal, David, Tetu, Bernard, Sahinalp, Cenk, Stein, Lincoln D, Fleshner, Neil, Shah, Sohrab P, Collins, Colin C, Hudson, Thomas J, Mcpherson, John D, Van Der Kwast, Theodorus and Bristow, Robert G (2015) Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nature Genetics, 47. 736–745. ISSN 1061-4036

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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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 24 Jul 2015 22:57
Last Modified: 22 Apr 2020 00:17
DOI: 10.1038/ng.3315

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