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Comprehensive genomic profiles of small cell lung cancer

机译:小细胞肺癌的综合基因组概况

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摘要

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
机译:我们已经对110种小细胞肺癌(SCLC)(最致命的人类癌症之一)的基因组进行了测序。在几乎所有分析的肿瘤中,我们发现TP53和RB1的双等位基因失活,有时是由于复杂的基因组重排。带有野生型RB1的两个肿瘤都有色杆菌病的证据,导致细胞周期蛋白D1过表达(由CCND1基因编码),揭示了Rb1失调的另一种机制。因此,在SCLC中肿瘤抑制物TP53和RB1的丧失是必须的。我们发现了TP73的体细胞基因组重排,该基因创建了该基因的致癌版本TP73Dex2 / 3。在极少数情况下,SCLC肿瘤表现出激酶基因突变,为个别患者提供了可能的治疗机会。最后,我们在25%的人类SCLC中观察到了NOTCH家族基因的失活突变。因此,在临床前SCLC小鼠模型中Notch信号的激活显着减少了肿瘤数量并延长了突变小鼠的生存期。此外,SCLC细胞中的Notch活性消除了神经内分泌基因的表达。这项对SCLC中体细胞基因组改变的首次全面研究揭示了几个关键的生物学过程,并确定了这种高度致死性癌症中的候选治疗靶标。

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  • 来源
    《Nature》 |2015年第7563期|47-53|共7页
  • 作者

    George Julie; Lim Jing Shan; Jang Se Jin; Cun Yupeng; Ozretic Luka; Kong Gu; Leenders Frauke; Lu Xin; Fernandez-Cuesta Lynnette; Bosco Graziella; Mueller Christian; Dahmen Ilona; Jahchan Nadine S.; Park Kwon-Sik; Yang Dian; Karnezis Anthony N.; Vaka Dedeepya; Torres Angela; Wang Maia Segura; Korbel Jan O.; Menon Roopika; Chun Sung-Min; Kim Deokhoon; Wilkerson Matt; Hayes Neil; Engelmann David; Puetzer Brigitte; Bos Marc; Michels Sebastian; Vlasic Ignacija; Seidel Danila; Pinther Berit; Schaub Philipp; Becker Christian; Altmueller Janine; Yokota Jun; Kohno Takashi; Iwakawa Reika; Tsuta Koji; Noguchi Masayuki; Muley Thomas; Hoffmann Hans; Schnabel Philipp A.; Petersen Iver; Chen Yuan; Soltermann Alex; Tischler Verena; Choi Chang-min; Kim Yong-Hee; Massion Pierre P.; Zou Yong; Jovanovic Dragana; Kontic Milica; Wright Gavin M.; Russell Prudence A.; Solomon Benjamin; Koch Ina; Lindner Michael; Muscarella Lucia A.; la Torre Annamaria; Field John K.; Jakopovic Marko; Knezevic Jelena; Castanos-Velez Esmeralda; Roz Luca; Pastorino Ugo; Brustugun Odd-Terje; Lund-Iversen Marius; Thunnissen Erik; Koehler Jens; Schuler Martin; Botling Johan; Sandelin Martin; Sanchez-Cespedes Montserrat; Salvesen Helga B.; Achter Viktor; Lang Ulrich; Bogus Magdalena; Schneider Peter M.; Zander Thomas; Ansen Sascha; Hallek Michael; Wolf Juergen; Vingron Martin; Yatabe Yasushi; Travis William D.; Nuernberg Peter; Reinhardt Christian; Perner Sven; Heukamp Lukas; Buettner Reinhard; Haas Stefan A.; Brambilla Elisabeth; Peifer Martin; Sage Julien; Thomas Roman K.;

  • 作者单位

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea|Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany;

    Hanyang Univ, Dept Pathol, Coll Med, Seoul 133791, South Korea;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Vancouver Gen Hosp, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany;

    Univ Hosp Bonn, Inst Pathol, Ctr Integrated Oncol Cologne Bonn, D-53127 Bonn, Germany;

    Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea|Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea;

    Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea;

    Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA;

    Univ N Carolina, UNC Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA;

    Univ Rostock, Med Ctr, Inst Expt Gene Therapy & Canc Res, D-18057 Rostock, Germany;

    Univ Rostock, Med Ctr, Inst Expt Gene Therapy & Canc Res, D-18057 Rostock, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany;

    Univ Hosp Cologne, Dept Internal Med, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany;

    Univ Cologne, CCG, D-50931 Cologne, Germany;

    Univ Cologne, CCG, D-50931 Cologne, Germany|Univ Hosp Cologne, Inst Human Genet, D-50931 Cologne, Germany;

    Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 1040045, Japan|Inst Predict & Personalized Med Canc IMPPC, Genom & Epigen Canc Predict Program, Barcelona 08916, Spain;

    Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 1040045, Japan;

    Natl Canc Ctr, Res Inst, Div Genome Biol, Chuo Ku, Tokyo 1040045, Japan;

    Natl Canc Ctr, Dept Pathol & Clin Labs, Chuo Ku, Tokyo 1040045, Japan;

    Univ Tsukuba, Fac Med, Dept Pathol, Tsukuba, Ibaraki 3058575, Japan;

    Univ Heidelberg Hosp, Thoraxklin, D-69126 Heidelberg, Germany|TLRC H, D-69126 Heidelberg, Germany;

    Univ Heidelberg Hosp, Thoraxklin, D-69126 Heidelberg, Germany;

    TLRC H, D-69126 Heidelberg, Germany|Heidelberg Univ, Inst Pathol, D-69120 Heidelberg, Germany;

    Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany;

    Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany;

    Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland;

    Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland;

    Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul 138736, South Korea;

    Univ Ulsan, Coll Med, Dept Thorac & Cardiovasc Surg, Asan Med Ctr, Seoul 138736, South Korea;

    Vanderbilt Ingram Canc Ctr, Thorac Program, Nashville, TN 37232 USA;

    Vanderbilt Ingram Canc Ctr, Thorac Program, Nashville, TN 37232 USA;

    Univ Belgrade, Sch Med, Univ Hosp Pulmonol, Clin Ctr Serbia, Belgrade 11000, Serbia;

    Univ Belgrade, Sch Med, Univ Hosp Pulmonol, Clin Ctr Serbia, Belgrade 11000, Serbia;

    St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Surg, Melbourne, Vic 3065, Australia;

    St Vincents Hosp, Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3065, Australia;

    Asklepios Fachkliniken, Comprehens Pneumol Ctr Munich, Asklepios Biobank Lungenerkrankungen, D-82131 Munich, Germany;

    Asklepios Fachkliniken, Comprehens Pneumol Ctr Munich, Asklepios Biobank Lungenerkrankungen, D-82131 Munich, Germany;

    IRCCS Casa Sollievo Sofferenza, Lab Oncol, I-71013 San Giovanni, Rotondo, Italy;

    IRCCS Casa Sollievo Sofferenza, Lab Oncol, I-71013 San Giovanni, Rotondo, Italy;

    Univ Liverpool, Canc Res Ctr, Roy Castle Lung Canc Res Programme, Dept Mol & Clin Canc Med,Inst Translat Med, Liverpool L69 3GA, Merseyside, England;

    Univ Zagreb, Sch Med, Dept Resp Dis Jordanovac, Univ Hosp Ctr Zagreb, Zagreb 10000, Croatia;

    Rudjer Boskovic Inst, Lab Translat Med, Zagreb 10000, Croatia;

    Charite Campus Mitte, Charite Comprehens Canc Ctr, D-10115 Berlin, Germany;

    Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Tumor Genom Unit, I-20133 Milan, Italy;

    Fdn IRCCS Ist Nazl Tumori, Dept Surg, Thorac Surg Unit, I-20133 Milan, Italy;

    Univ Oslo, Fac Med, Inst Clin Med, N-0424 Oslo, Norway|Oslo Univ Hosp, Norwegian Radium Hosp, Dept Oncol, N-0310 Oslo, Norway;

    Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway;

    Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands;

    Univ Hosp Essen, Dept Med Oncol, West German Canc Ctr, D-45147 Essen, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany;

    Univ Hosp Essen, Dept Med Oncol, West German Canc Ctr, D-45147 Essen, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany;

    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden|Uppsala Univ, Dept Med Sci Resp Allergy & Sleep Res, S-75185 Uppsala, Sweden;

    Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden|Uppsala Univ, Dept Med Sci Resp Allergy & Sleep Res, S-75185 Uppsala, Sweden;

    Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Genes & Canc Grp, Barcelona 08908, Spain;

    Univ Bergen, Ctr Canc Biomarkers, Dept Clin Sci, N-5058 Bergen, Norway|Haukeland Hosp, Dept Gynecol & Obstet, N-5058 Bergen, Norway;

    Univ Cologne, Ctr Comp, D-50931 Cologne, Germany;

    Univ Cologne, Ctr Comp, D-50931 Cologne, Germany|Univ Cologne, Dept Informat, D-50931 Cologne, Germany;

    Univ Cologne, Dept Informat, D-50931 Cologne, Germany;

    Univ Cologne, Inst Legal Med, D-50823 Cologne, Germany;

    Univ Hosp Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne Bonn, Gastrointestinal Canc Grp Cologne, D-50937 Cologne, Germany;

    Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany;

    Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany|Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany;

    Univ Hosp Cologne, Ctr Integrated Oncol Cologne Bonn, Dept Internal Med 1, D-50937 Cologne, Germany;

    Max Planck Inst Mol Genet, Computat Mol Biol Grp, D-14195 Berlin, Germany;

    Aichi Canc Ctr, Dept Pathol & Mol Diagnost, Nagoya, Aichi 4648681, Japan;

    Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA;

    Univ Cologne, CCG, D-50931 Cologne, Germany|Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany|Univ Cologne, CMMC, D-50931 Cologne, Germany;

    Univ Hosp Cologne, Dept Internal Med, D-50931 Cologne, Germany;

    Univ Ulsan, Coll Med, Asan Med Ctr, Ctr Canc Genome Discovery, Seoul 138736, South Korea;

    Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany;

    Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany;

    Max Planck Inst Mol Genet, Computat Mol Biol Grp, D-14195 Berlin, Germany;

    Univ Grenoble 1, Inst Albert Bonniot 38043, Dept Pathol, CHU Grenoble,INSERM,U823, F-38043 Grenoble, France;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany|Univ Cologne, CMMC, D-50931 Cologne, Germany;

    Stanford Univ, Dept Pediat, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Stanford, CA 94305 USA;

    Univ Cologne, Fac Med, Dept Translat Genom, Ctr Integrated Oncol Cologne Bonn, D-50931 Cologne, Germany|Univ Hosp Cologne, Dept Pathol, D-50937 Cologne, Germany;

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