pgen.1007001.pdf (5.65 MB)
Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data
journal contributionposted on 2021-08-17, 11:57 authored by Niedzica Camacho, Peter Van Loo, Sandra Edwards, Jonathan D Kay, Lucy Matthews, Kerstin Haase, Jeremy Clark, Nening Dennis, Sarah Thomas, Barbara Kremeyer, Jorge Zamora, Adam P Butler, Gunes Gundem, Sue Merson, Hayley Luxton, Steve Hawkins, Mohammed Ghori, Luke Marsden, Adam Lambert, Katalin Karaszi, Gill Pelvender, Charlie E Massie, ZSofia Kote-Jarai, Keiran Raine, David Jones, William J Howat, Steven Hazell, Naomi Livni, Cyril Fisher, Christopher Ogden, Pardeep Kumar, Alan Thompson, David Nicol, Erik Mayer, Tim Dudderidge, Yongwei Yu, Hongwei Zhang, Nimish C Shah, Vincent J Gnanapragasam, The CRUK-ICGC Prostate Group, William Isaacs, Tapio Visakorpi, Freddie Hamdy, Dan Berney, Clare Verrill, Anne Y Warren, David C Wedge, Andrew G Lynch, Christopher S Foster, Yong Jie Lu, G Steven Bova, Hayley C Whitaker, Ultan McDermott, David E Neal, Rosalind Eeles, Colin S Cooper, Daniel S Brewer
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.