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Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

Title: Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data
Authors: Camacho, N
Van Loo, P
Edwards, S
Kay, JD
Matthews, L
Haase, K
Clark, J
Dennis, N
Thomas, S
Kremeyer, B
Zamora, J
Butler, AP
Gundem, G
Merson, S
Luxton, H
Hawkins, S
Ghori, M
Marsden, L
Lambert, A
Karaszi, K
Pelvender, G
Massie, CE
Kote-Jarai, Z
Raine, K
Jones, D
Howat, WJ
Hazell, S
Livni, N
Fisher, C
Ogden, C
Kumar, P
Thompson, A
Nicol, D
Mayer, E
Dudderidge, T
Yu, Y
Zhang, H
Shah, NC
Gnanapragasam, VJ
CRUK-ICGC Prostate Group
Isaacs, W
Visakorpi, T
Hamdy, F
Berney, D
Verrill, C
Warren, AY
Wedge, DC
Lynch, AG
Foster, CS
Lu, YJ
Bova, GS
Whitaker, HC
McDermott, U
Neal, DE
Eeles, R
Cooper, CS
Brewer, DS
Item Type: Journal Article
Abstract: 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.
Issue Date: 25-Sep-2017
Date of Acceptance: 28-Aug-2017
URI: http://hdl.handle.net/10044/1/57967
DOI: https://dx.doi.org/10.1371/journal.pgen.1007001
ISSN: 1553-7390
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Genetics
Volume: 13
Issue: 9
Copyright Statement: © 2017 Camacho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RDB04 79560
RD207
Keywords: Alleles
DNA Copy Number Variations
Genome, Human
Genomics
High-Throughput Nucleotide Sequencing
Humans
Male
Prostatectomy
Prostatic Neoplasms
RNA, Long Noncoding
Sequence Analysis, DNA
Sequence Deletion
CRUK-ICGC Prostate Group
0604 Genetics
Developmental Biology
Publication Status: Published online
Conference Place: United States
Article Number: e1007001
Appears in Collections:Division of Surgery
Faculty of Medicine



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