title: Whole-genome landscape of pancreatic neuroendocrine tumours.
abstract: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.lastname: Scarpa
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.|The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Katia
authors.initials: K
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.initials: P
authors.lastname: Bailey
authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.initials: RT
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
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authors.initials: AL
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.initials: DK
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.initials: A
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Borislav
authors.initials: B
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authors.affiliation: Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.initials: KO
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authors.affiliation: Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.initials: MC
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.initials: AN
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.initials: E
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.|Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy.
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authors.affiliation: Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia.
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authors.initials: CJ
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China.
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.
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authors.initials: NB
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authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.|Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK.
authors.forename: Fraser
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authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.|Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA.
authors.forename: Marie-Claude
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authors.affiliation: Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA.
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authors.affiliation: Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia.
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authors.affiliation: Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia.
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authors.affiliation: Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia.
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authors.affiliation: Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia.
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authors.initials: RR
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|University of Sydney. Sydney, New South Wales 2006, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.
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authors.initials: JG
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authors.affiliation: Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Merrett
authors.affiliation: Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia.
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authors.affiliation: Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
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authors.initials: NQ
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authors.affiliation: School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia.|St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia.|Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia.
authors.forename: Nikolajs
authors.initials: N
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authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Massimo
authors.initials: M
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authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Michele
authors.initials: M
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authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
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authors.initials: G
authors.lastname: Van Buren
authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Partelli
authors.affiliation: ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Matteo
authors.initials: M
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authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.
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authors.affiliation: The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|University of Sydney. Sydney, New South Wales 2006, Australia.
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authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
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authors.initials: DA
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authors.affiliation: Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA.
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authors.initials: RA
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authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.
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authors.initials: EA
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authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Claudio
authors.initials: C
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authors.forename: Giampaolo
authors.initials: G
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authors.affiliation: Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pederzoli
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.|Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK.|West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK.|The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia.|Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia.|South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.affiliation: University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
mesh_terms: D001483:Base Sequence; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000235:genetics*; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism
chemical_list: D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase