Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data
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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.
Camacho , 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.1007001
© 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.
We 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).
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