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dc.contributor.authorCamacho, Niedzica
dc.contributor.authorVan Loo, Peter
dc.contributor.authorEdwards, Sandra
dc.contributor.authorKay, Jonathan D.
dc.contributor.authorMatthews, Lucy
dc.contributor.authorHaase, Kerstin
dc.contributor.authorClark, Jeremy
dc.contributor.authorDennis, Nening
dc.contributor.authorThomas, Sarah
dc.contributor.authorKremeyer, Barbara
dc.contributor.authorZamora, Jorge
dc.contributor.authorButler, Adam P.
dc.contributor.authorGundem, Gunes
dc.contributor.authorMerson, Sue
dc.contributor.authorLuxton, Hayley
dc.contributor.authorHawkins, Steve
dc.contributor.authorGhori, Mohammed
dc.contributor.authorMarsden, Luke
dc.contributor.authorLambert, Adam
dc.contributor.authorKaraszi, Katalin
dc.contributor.authorPelvender, Gill
dc.contributor.authorMassie, Charlie E.
dc.contributor.authorKote-Jarai, ZSofia
dc.contributor.authorRaine, Keiran
dc.contributor.authorJones, David
dc.contributor.authorHowat, William J.
dc.contributor.authorHazell, Steven
dc.contributor.authorLivni, Naomi
dc.contributor.authorFisher, Cyril
dc.contributor.authorOgden, Christopher
dc.contributor.authorKumar, Pardeep
dc.contributor.authorThompson, Alan
dc.contributor.authorNicol, David
dc.contributor.authorMayer, Erik
dc.contributor.authorDudderidge, Tim
dc.contributor.authorYu, Yongwei
dc.contributor.authorZhang, Hongwei
dc.contributor.authorShah, Nimish C.
dc.contributor.authorGnanapragasam, Vincent J.
dc.contributor.authorGroup, The CRUK-ICGC Prostate
dc.contributor.authorIsaacs, William
dc.contributor.authorVisakorpi, Tapio
dc.contributor.authorHamdy, Freddie
dc.contributor.authorBerney, Dan
dc.contributor.authorVerrill, Clare
dc.contributor.authorWarren, Anne Y.
dc.contributor.authorWedge, David C.
dc.contributor.authorLynch, Andrew G.
dc.contributor.authorFoster, Christopher S.
dc.contributor.authorLu, Yong Jie
dc.contributor.authorBova, G. Steven
dc.contributor.authorWhitaker, Hayley C.
dc.contributor.authorMcDermott, Ultan
dc.contributor.authorNeal, David E.
dc.contributor.authorEeles, Rosalind
dc.contributor.authorCooper, Colin S.
dc.contributor.authorBrewer, Daniel S.
dc.date.accessioned2017-10-06T09:30:10Z
dc.date.available2017-10-06T09:30:10Z
dc.date.issued2017-09-25
dc.identifier.citationCamacho , N , Van Loo , P , Edwards , S , Kay , J D , Matthews , L , Haase , K , Clark , J , Dennis , N , Thomas , S , Kremeyer , B , Zamora , J , Butler , A P , Gundem , G , Merson , S , Luxton , H , Hawkins , S , Ghori , M , Marsden , L , Lambert , A , Karaszi , K , Pelvender , G , Massie , C E , Kote-Jarai , Z S , Raine , K , Jones , D , Howat , W J , Hazell , S , Livni , N , Fisher , C , Ogden , C , Kumar , P , Thompson , A , Nicol , D , Mayer , E , Dudderidge , T , Yu , Y , Zhang , H , Shah , N C , Gnanapragasam , V J , Group , T C R U K-I C G C P , Isaacs , W , Visakorpi , T , Hamdy , F , Berney , D , Verrill , C , Warren , A Y , Wedge , D C , Lynch , A G , Foster , C S , Lu , Y J , Bova , G S , Whitaker , H C , McDermott , U , Neal , D E , Eeles , R , Cooper , C S & Brewer , D S 2017 , ' Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data ' PLoS Genetics , vol 13 , no. 9 , e1007001 . DOI: 10.1371/journal.pgen.1007001en
dc.identifier.issn1553-7390
dc.identifier.otherPURE: 251169556
dc.identifier.otherPURE UUID: 2045f4cf-cd80-4938-b909-9cd5486870f8
dc.identifier.otherRIS: urn:3A9C75920B3AC3700681F0951DEA0B5B
dc.identifier.urihttp://hdl.handle.net/10023/11812
dc.identifier.urihttp://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007001#sec025en
dc.descriptionWe acknowledge support from Cancer Research UK (C5047/A22530, C309/A11566, C368/A6743, A368/A7990, C14303/A17197) and the Dallaglio Foundation. We also acknowledge support from the National Institute of Health Research (NIHR) (The Biomedical Research Centre at The Institute of Cancer Research & The Royal Marsden NHS Foundation Trust and the project "Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT)" [G0500966/75466]). We thank the Wellcome Trust, Bob Champion Cancer Trust, The Orchid Cancer appeal, The RoseTrees Trust, The North West Cancer Research Fund, Big C, The King family, and The Masonic Charitable Foundation for funding. This research is supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202).en
dc.description.abstractA 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.en
dc.language.isoeng
dc.relation.ispartofPLoS Geneticsen
dc.rights© 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.en
dc.subjectQH426 Geneticsen
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectDASen
dc.subject.lccQH426en
dc.subject.lccRC0254en
dc.titleAppraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence dataen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Statisticsen
dc.contributor.institutionUniversity of St Andrews. Population & Behavioural Science Divisionen
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pgen.1007001
dc.description.statusPeer revieweden


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