Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data
Creators: name: Camacho, Niedzica
name: Van Loo, Peter
name: Edwards, Sandra
name: Kay, Jonathan D
name: Matthews, Lucy
name: Haase, Kerstin
name: Clark, Jeremy
name: Dennis, Nening
name: Thomas, Sarah
name: Kremeyer, Barbara
name: Zamora, Jorge
name: Butler, Adam P
name: Gundem, Gunes
name: Merson, Sue
name: Luxton, Hayley
name: Hawkins, Steve
name: Ghori, Mohammed
name: Marsden, Luke
name: Lambert, Adam
name: Karaszi, Katalin
name: Pelvender, Gill
name: Massie, Charlie E
name: Kote-Jarai, ZSofia
name: Raine, Keiran
name: Jones, David
name: Howat, William J
name: Hazell, Steven
name: Livni, Naomi
name: Fisher, Cyril
name: Ogden, Christopher
name: Kumar, Pardeep
name: Thompson, Alan
name: Nicol, David
name: Mayer, Erik
name: Dudderidge, Tim
name: Yu, Yongwei
name: Zhang, Hongwei
name: Shah, Nimish C
name: Gnanapragasam, Vincent J
name: Group, The CRUK-ICGC Prostate
name: Isaacs, William
name: Visakorpi, Tapio
name: Hamdy, Freddie
name: Berney, Dan
name: Verrill, Clare
name: Warren, Anne Y
name: Wedge, David C
name: Lynch, Andrew G
name: Foster, Christopher S
name: Lu, Yong Jie
name: Bova, G Steven
name: Whitaker, Hayley C
name: McDermott, Ultan
name: Neal, David E
name: Eeles, Rosalind
name: Cooper, Colin S
name: Brewer, Daniel S
Publisher: name: The Francis Crick Institute
Year: 2021
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Ecology,Evolution & Ethology
subject: Ecology,Evolution &amp; Ethology
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology

description: 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.