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Whole-genome landscape of pancreatic neuroendocrine tumours

机译：胰腺神经内分泌肿瘤的全基因组格局

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摘要

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.
机译：胰腺神经内分泌肿瘤（PanNETs）的诊断由于更灵敏的检测方法而在增加，并且这种增加为临床管理带来了挑战。我们对102个主要PanNET进行了全基因组测序，并定义了表征其发病机理的基因组事件。在这里，我们描述了它们具有的突变特征，包括G缺乏：C> T：由于MUTYH失活而导致的碱基切除修复，MUTYH编码DNA糖基化酶。临床上零星的PanNETs包含的种系突变比例超出预期，包括DNA修复基因MUTYH，CHEK2和BRCA2中以前未报道的突变。连同MEN1和VHL中的突变，这些突变发生在17％的患者中。体细胞突变，包括点突变和基因融合，通常在涉及四个主要途径的基因中发现：染色质重塑，DNA损伤修复，mTOR信号激活（包括先前未描述的EWSR1基因融合）和端粒维持。此外，我们的基因表达分析确定了与缺氧和HIF信号传导相关的肿瘤亚组。

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  • 来源
    《Nature》 |2017年第7643期|65-71|共7页
  • 作者

    Scarpa Aldo; Chang David K.; Nones Katia; Corbo Vincenzo; Patch Ann-Marie; Bailey Peter; Lawlor Rita T.; Johns Amber L.; Miller David K.; Mafficini Andrea; Rusev Borislav; Scardoni Maria; Antonello Davide; Barbi Stefano; Sikora Katarzyna O.; Cingarlini Sara; Vicentini Caterina; McKay Skye; Quinn Michael C. J.; Bruxner Timothy J. C.; Christ Angelika N.; Harliwong Ivon; Idrisoglu Senel; McLean Suzanne; Nourse Craig; Nourbakhsh Ehsan; Wilson Peter J.; Anderson Matthew J.; Fink J. Lynn; Newell Felicity; Waddell Nick; Holmes Oliver; Kazakoff Stephen H.; Leonard Conrad; Wood Scott; Xu Qinying; Nagaraj Shivashankar Hiriyur; Amato Eliana; Dalai Irene; Bersanif Samantha; Cataldo Ivana; Tos Angelo P. Dei; Capelli Paola; Davi Maria Vittoria; Landoni Luca; Malpaga Anna; Miotto Marco; Whitehall Vicki L. J.; Leggett Barbara A.; Harris Janelle L.; Harris Jonathan; Jones Marc D.; Humphris Jeremy; Chantrill Lorraine A.; Chin Venessa; Nagrial Adnan M.; Pajic Marina; Scarlett Christopher J.; Pinho Andreia; Rooman Ilse; Toon Christopher; Wu Jianmin; Pinese Mark; Cowley Mark; Barbour Andrew; Mawson Amanda; Humphrey Emily S.; Colvin Emily K.; Chou Angela; Lovell Jessica A.; Jamieson Nigel B.; Duthie Fraser; Gingras Marie-Claude; Fisher William E.; Dagg Rebecca A.; Lau Loretta M. S.; Lee Michael; Pickett Hilda A.; Reddel Roger R.; Samra Jaswinder S.; Kench James G.; Merrett Neil D.; Epari Krishna; Nguyen Nam Q.; Zeps Nikolajs; Falconi Massimo; Simbolo Michele; Butturini Giovanni; Van Buren George; Partelli Stefano; Fassan Matteo; Khanna Kum Kum; Gill Anthony J.; Wheeler David A.; Gibbs Richard A.; Musgrove Elizabeth A.; Bassi Claudio; Tortora Giampaolo; Pederzoli Paolo; Pearson John V.; Waddell Nicola; Biankin Andrew V.; Grimmond Sean M.;

  • 作者单位

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|West Scotland Pancreat Unit, Glasgow Royal Infirm, Glasgow G31 2ER, Lanark, Scotland|Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW, Australia|Univ New South Wales, South Western Sydney Clin Sch, Fac Med, Liverpool, NSW 2170, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Med Oncol, Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy|Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ Padua, Gen Hosp Treviso, Dept Med, Padua, Italy;

    Univ & Hosp Trust Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Endocrinol Sect, Dept Med, Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia|Pathol Queensland, Brisbane, Qld 4006, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia|Royal Brisbane & Womens Hosp, Dept Gastroenterol & Hepatol, Brisbane, Qld 4006, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia;

    Queensland Univ Technol, Inst Hlth Biomed Innovat, Brisbane, Qld, Australia;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Univ Newcastle, Sch Environm & Life Sci, Ourimbah, NSW 2258, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Vrije Univ Brussel, Oncol Res Ctr, Brussels, Belgium;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Key Lab Carcinogenesis & Translat Res Minist Educ, Peking Univ Canc Hosp Inst, Ctr Canc Bioinformat, Beijing 100142, Peoples R China;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Princess Alexandra Hosp, Dept Surg, Ipswich Rd, Brisbane, Qld 4102, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Dept Anat Pathol St Vincents Hosp, Sydney, NSW 2010, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|West Scotland Pancreat Unit, Glasgow Royal Infirm, Glasgow G31 2ER, Lanark, Scotland|Univ Glasgow, Sch Med, Coll Med, Acad Surg Unit, Glasgow G4 OSF, Lanark, Scotland;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|Queen Elizabeth Univ Hosp, Greater Glasgow Clyde NHS, Dept Pathol, Glasgow G51 4TF, Lanark, Scotland;

    Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, 1 Baylor Plaza, MS226, Houston, TX 77030 USA|Michael DeBakey Dept Surg & Elkins Pancreas Ctr, Baylor Coll Med, 1 Baylor Plaza, Houston, TX 77030 USA;

    Michael DeBakey Dept Surg & Elkins Pancreas Ctr, Baylor Coll Med, 1 Baylor Plaza, Houston, TX 77030 USA;

    Childrens Hosp, Westmead, NSW 2145, Australia;

    Childrens Hosp, Westmead, NSW 2145, Australia;

    Univ Sydney, Med Res Inst, Westmead, NSW, Australia;

    Univ Sydney, Med Res Inst, Westmead, NSW, Australia;

    Univ Sydney, Med Res Inst, Westmead, NSW, Australia;

    Royal N Shore Hosp, Dept Surg, St Leonards, NSW, Australia|Univ Sydney, New South Wales 2006, Sydney, NSW 2006, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Univ Sydney, New South Wales 2006, Sydney, NSW 2006, Australia|Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Camperdown, NSW 2050, Australia;

    Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW, Australia|Univ Western Sydney, Sch Med, Penrith, NSW 2175, Australia;

    Fremantle Hosp, Dept Surg, Alma St, Fremantle, WA 6160, Australia;

    Royal Adelaide Hosp, Dept Gastroenterol, N Terrace, Adelaide, SA 5000, Australia;

    Univ Western Australia, Sch Surg, M507, 35 Stirling Highway, Nedlands, WA 6009, Australia|St John God Pathol, 12 Salvado Rd, Subiaco, WA 6008, Australia|St John God Subiaco Hosp, Bendat Family Comprehens Canc Ctr, Subiaco, WA 6008, Australia;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Michael DeBakey Dept Surg & Elkins Pancreas Ctr, Baylor Coll Med, 1 Baylor Plaza, Houston, TX 77030 USA;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, IARC Net Ctr Appl Res Canc, I-37134 Verona, Italy;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia;

    Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Univ Sydney, New South Wales 2006, Sydney, NSW 2006, Australia;

    Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, 1 Baylor Plaza, MS226, Houston, TX 77030 USA;

    Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, 1 Baylor Plaza, MS226, Houston, TX 77030 USA;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    Univ & Hosp Trust Verona, Med Oncol, Verona, Italy;

    Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    QIMR Berghofer Med Res Inst, Herston, Qld, Australia|Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, St Lucia, Qld, Australia;

    Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Garscube Estate,Switchback Rd, Glasgow G61 1QH, Lanark, Scotland|West Scotland Pancreat Unit, Glasgow Royal Infirm, Glasgow G31 2ER, Lanark, Scotland|Univ New South Wales, Garvan Inst Med Res, Canc Div, Kinghorn Canc Ctr, 384 Victoria St,Sydney, Darlinghurst, NSW, Australia|Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW, Australia|Univ New South Wales, South Western Sydney Clin Sch, Fac Med, Liverpool, NSW 2170, Australia;

    Univ Melbourne, Univ Melbourne Ctr Canc Res, Victoria, Melbourne 3010, Australia;

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