Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.

Comprehensive genomic profiles of small cell lung cancer.

George J¹, Lim JS², Jang SJ³, Cun Y¹, Ozretić L⁴, Kong G⁵, Leenders F¹, Lu X¹, Fernández-Cuesta L¹, Bosco G¹, Müller C¹, Dahmen I¹, Jahchan NS², Park KS², Yang D², Karnezis AN⁶, Vaka D², Torres A², Wang MS⁷, Korbel JO⁷, Menon R⁸, Chun SM³, Kim D⁹, Wilkerson M¹⁰, Hayes N¹¹, Engelmann D¹², Pützer B¹², Bos M¹, Michels S¹³, Vlasic I¹⁴, Seidel D¹, Pinther B¹, Schaub P¹, Becker C¹⁵, Altmüller J¹⁶, Yokota J¹⁷, Kohno T¹⁸, Iwakawa R¹⁸, Tsuta K¹⁹, Noguchi M²⁰, Muley T²¹, Hoffmann H²², Schnabel PA²³, Petersen I²⁴, Chen Y²⁴, Soltermann A²⁵, Tischler V²⁵, Choi CM²⁶, Kim YH²⁷, Massion PP²⁸, Zou Y²⁸, Jovanovic D²⁹, Kontic M²⁹, Wright GM³⁰, Russell PA³¹, Solomon B³², Koch I³³, Lindner M³³, Muscarella LA³⁴, la Torre A³⁴, Field JK³⁵, Jakopovic M³⁶, Knezevic J³⁷, Castaños-Vélez E³⁸, Roz L³⁹, Pastorino U⁴⁰, Brustugun OT⁴¹, Lund-Iversen M⁴², Thunnissen E⁴³, Köhler J⁴⁴, Schuler M⁴⁴, Botling J⁴⁵, Sandelin M⁴⁵, Sanchez-Cespedes M⁴⁶, Salvesen HB⁴⁷, Achter V⁴⁸, Lang U⁴⁹, Bogus M⁵⁰, Schneider PM⁵⁰, Zander T⁵¹, Ansén S¹³, Hallek M⁵², Wolf J¹³, Vingron M⁵³, Yatabe Y⁵⁴, Travis WD⁵⁵, Nürnberg P⁵⁶, Reinhardt C¹⁴, Perner S⁹, Heukamp L⁴, Büttner R⁴, Haas SA⁵³, Brambilla E⁵⁷, Peifer M⁵⁸, Sage J², Thomas RK⁵⁹.

Author information

1: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
2: Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA.
3: Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
4: Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.
5: Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea.
6: Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada.
7: European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany.
8: Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany.
9: Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
10: Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA.
11: UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA.
12: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany.
13: Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany.
14: Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany.
15: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
16: 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
17: 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain.
18: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan.
19: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan.
20: Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
21: 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany.
22: Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany.
23: 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany.
24: Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany.
25: Institute of Surgical Pathology, University Hospital Zürich, 8091 Zürich, Switzerland.
26: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
27: Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea.
28: Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA.
29: University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia.
30: Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia.
31: Department of Pathology, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia.
32: Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia.
33: Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting 82131, Germany.
34: Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy.
35: Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre, 200 London Road, L69 3GA Liverpool, UK.
36: University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, 10000 Zagreb, Croatia.
37: Laboratory for Translational Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
38: Charité Comprehensive Cancer Center, Charité Campus Mitte, 10115 Berlin, Germany.
39: Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS - Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy.
40: Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
41: 1] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway. [2] Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
42: Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway.
43: Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
44: 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
45: Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden.
46: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain.
47: 1] Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, N-5058 Bergen, Norway. [2] Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway.
48: Computing Center, University of Cologne, 50931 Cologne, Germany.
49: 1] Computing Center, University of Cologne, 50931 Cologne, Germany. [2] Department of Informatics, University of Cologne, 50931 Cologne, Germany.
50: Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany.
51: Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50937 Cologne, Germany.
52: 1] Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
53: Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
54: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 464-8681 Nagoya, Japan.
55: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.
56: 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. [3] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
57: Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France.
58: 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
59: 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.

Abstract

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, TP73Δex2/3. 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.

PMID:: 26168399
PMCID:: PMC4861069
DOI:: 10.1038/nature14664

[Indexed for MEDLINE]

Free PMC Article

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Extended Data Figure 10

Notch is a tumour suppressor in SCLC regulating neuroendocrine differentiation

a, Somatic mutations identified in NOTCH3 and NOTCH4 are mapped to the protein domains. Damaging mutations are highlighted in red. Mutations found in murine SCLC tumours are highlighted in blue. b, Quantification of tumour lesions and per cent tumour area to lung in TKO (n = 5) and TKO;N1ICD (n = 4) mice 3 months after Ad-Cre instillation. Statistical significance was determined by two-tailed unpaired Student’s t-test. c, Representative immunohistochemistry for GFP or tdTomato in lungs from TKO;Rosa26^mT/mG mice approximately 6 months after tumour induction. Left scale bar, 500 µm; right and middle: scale bar, 50 µm. d, Representative immunostaining for Notch2 in lungs from TKO;Rosa26^N2ICD mice approximately 6 months after tumour induction. Left scale bar, 500 µm; right scale bar, 50 µm. e, Quantification of the per cent recombination at the Rosa26 locus in TKO;Rosa26^mT/mG (n = 6) and TKO;Rosa26^N2ICD mice (n = 10; two-tailed unpaired Student’s t-test). f, Cell viability assay of the human SCLC cell line NJH29 transfected with a N1ICD (Notch1) expression plasmid or empty vector control (Ctrl) (3 independent biological replicas with 3 technical replicas each). Fold growth was normalized to day 0; representative images were taken on day 6. Scale bar, 50 µm. g, Immunohistochemistry staining in FFPE embedded tissues of TKO and TKO;N2ICD mice. Scale bar, 50 µm. h, Quantitative RT–PCR validation of Notch1 induction and the expression of common Notch target genes after N1ICD transfection in murine SCLC cells (three biological replicas; two-tailed paired Student’s t-test). i, Mouse SCLC cells transfected with control or N1ICD (Notch1) were analysed 48 h later by gene expression microarrays. Gene Set Enrichment Analysis (GSEA) was performed on these data; selected significant gene sets are displayed. j, k, EdU analysis of mouse (j) and human (k) SCLC cells (three independent biological replicas with three technical replicas each; two-tailed paired Student’s t-test). *P < 0.05; **P < 0.01; ***P < 0.001. Data are represented as mean ± s.d.

Comprehensive genomic profiles of small cell lung cancer

Nature. 2015 Aug 6;524(7563):47-53.