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Comprehensive genomic profiles of small cell lung cancer

Author

Listed:
  • Julie George

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Jing Shan Lim

    (Stanford University)

  • Se Jin Jang

    (University of Ulsan College of Medicine, Asan Medical Center)

  • Yupeng Cun

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Luka Ozretić

    (University Hospital Cologne)

  • Gu Kong

    (College of Medicine, Hanyang University)

  • Frauke Leenders

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Xin Lu

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Lynnette Fernández-Cuesta

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
    †Present address: Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), 69008 Lyon, France.)

  • Graziella Bosco

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Christian Müller

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Ilona Dahmen

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Nadine S. Jahchan

    (Stanford University)

  • Kwon-Sik Park

    (Stanford University)

  • Dian Yang

    (Stanford University)

  • Anthony N. Karnezis

    (Vancouver General Hospital, Terry Fox laboratory)

  • Dedeepya Vaka

    (Stanford University)

  • Angela Torres

    (Stanford University)

  • Maia Segura Wang

    (European Molecular Biology Laboratory, Genome Biology Unit)

  • Jan O. Korbel

    (European Molecular Biology Laboratory, Genome Biology Unit)

  • Roopika Menon

    (Institute of Pathology, Center of Integrated Oncology Cologne–Bonn, University Hospital of Bonn)

  • Sung-Min Chun

    (University of Ulsan College of Medicine, Asan Medical Center)

  • Deokhoon Kim

    (Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center)

  • Matt Wilkerson

    (Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill)

  • Neil Hayes

    (UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill)

  • David Engelmann

    (Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center)

  • Brigitte Pützer

    (Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center)

  • Marc Bos

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Sebastian Michels

    (Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne)

  • Ignacija Vlasic

    (University Hospital of Cologne)

  • Danila Seidel

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Berit Pinther

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Philipp Schaub

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne)

  • Christian Becker

    (Cologne Center for Genomics (CCG), University of Cologne)

  • Janine Altmüller

    (Cologne Center for Genomics (CCG), University of Cologne
    Institute of Human Genetics, University Hospital Cologne)

  • Jun Yokota

    (National Cancer Center Research Institute, Chuo-ku
    Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC))

  • Takashi Kohno

    (National Cancer Center Research Institute, Chuo-ku)

  • Reika Iwakawa

    (National Cancer Center Research Institute, Chuo-ku)

  • Koji Tsuta

    (National Cancer Center Hospital Chuo-ku)

  • Masayuki Noguchi

    (Faculty of Medicine, University of Tsukuba)

  • Thomas Muley

    (Thoraxklinik at University Hospital Heidelberg
    Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL))

  • Hans Hoffmann

    (Thoraxklinik at University Hospital Heidelberg)

  • Philipp A. Schnabel

    (Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL)
    Institute of Pathology, University of Heidelberg)

  • Iver Petersen

    (Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University)

  • Yuan Chen

    (Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University)

  • Alex Soltermann

    (Institute of Surgical Pathology, University Hospital Zürich)

  • Verena Tischler

    (Institute of Surgical Pathology, University Hospital Zürich)

  • Chang-min Choi

    (University of Ulsan College of Medicine, Asan Medical Center)

  • Yong-Hee Kim

    (University of Ulsan College of Medicine, Asan Medical Center)

  • Pierre P. Massion

    (Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640)

  • Yong Zou

    (Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640)

  • Dragana Jovanovic

    (University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade)

  • Milica Kontic

    (University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade)

  • Gavin M. Wright

    (St. Vincent’s Hospital, Peter MacCallum Cancer Centre)

  • Prudence A. Russell

    (St. Vincent’s Hospital, Peter MacCallum Cancer Centre)

  • Benjamin Solomon

    (Peter MacCallum Cancer Centre)

  • Ina Koch

    (Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting)

  • Michael Lindner

    (Asklepios Biobank für Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken München-Gauting)

  • Lucia A. Muscarella

    (Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini)

  • Annamaria la Torre

    (Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini)

  • John K. Field

    (Roy Castle Lung Cancer Research Programme, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre)

  • Marko Jakopovic

    (University of Zagreb, School of Medicine, University Hospital Center Zagreb)

  • Jelena Knezevic

    (Laboratory for Translational Medicine, Rudjer Boskovic Institute)

  • Esmeralda Castaños-Vélez

    (Charité Comprehensive Cancer Center, Charité Campus Mitte)

  • Luca Roz

    (Tumor Genomics Unit, Fondazione IRCCS — Istituto Nazionale Tumori)

  • Ugo Pastorino

    (Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori)

  • Odd-Terje Brustugun

    (Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
    Norwegian Radium Hospital, Oslo University Hospital)

  • Marius Lund-Iversen

    (Norwegian Radium Hospital, Oslo University Hospital)

  • Erik Thunnissen

    (VU University Medical Center)

  • Jens Köhler

    (West German Cancer Center, University Hospital Essen
    German Cancer Consortium (DKTK))

  • Martin Schuler

    (West German Cancer Center, University Hospital Essen
    German Cancer Consortium (DKTK))

  • Johan Botling

    (Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University)

  • Martin Sandelin

    (Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University)

  • Montserrat Sanchez-Cespedes

    (Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL))

  • Helga B. Salvesen

    (Center for Cancer Biomarkers, University of Bergen
    Haukeland University Hospital)

  • Viktor Achter

    (Computing Center, University of Cologne)

  • Ulrich Lang

    (Computing Center, University of Cologne
    University of Cologne)

  • Magdalena Bogus

    (Institute of Legal Medicine, University of Cologne)

  • Peter M. Schneider

    (Institute of Legal Medicine, University of Cologne)

  • Thomas Zander

    (Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne–Bonn, University Hospital of Cologne)

  • Sascha Ansén

    (Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne)

  • Michael Hallek

    (Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne)

  • Jürgen Wolf

    (Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne)

  • Martin Vingron

    (Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics)

  • Yasushi Yatabe

    (Aichi Cancer Center)

  • William D. Travis

    (Memorial Sloan-Kettering Cancer Center)

  • Peter Nürnberg

    (Cologne Center for Genomics (CCG), University of Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
    Center for Molecular Medicine Cologne (CMMC), University of Cologne)

  • Christian Reinhardt

    (University Hospital of Cologne)

  • Sven Perner

    (Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center)

  • Lukas Heukamp

    (University Hospital Cologne)

  • Reinhard Büttner

    (University Hospital Cologne)

  • Stefan A. Haas

    (Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics)

  • Elisabeth Brambilla

    (CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043)

  • Martin Peifer

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
    Center for Molecular Medicine Cologne (CMMC), University of Cologne)

  • Julien Sage

    (Stanford University)

  • Roman K. Thomas

    (Center of Integrated Oncology Cologne–Bonn, Medical Faculty, University of Cologne
    University Hospital Cologne)

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.

Suggested Citation

  • Julie George & Jing Shan Lim & Se Jin Jang & Yupeng Cun & Luka Ozretić & Gu Kong & Frauke Leenders & Xin Lu & Lynnette Fernández-Cuesta & Graziella Bosco & Christian Müller & Ilona Dahmen & Nadine S. , 2015. "Comprehensive genomic profiles of small cell lung cancer," Nature, Nature, vol. 524(7563), pages 47-53, August.
    • Handle: RePEc:nat:nature:v:524:y:2015:i:7563:d:10.1038_nature14664
    DOI: 10.1038/nature14664
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    Cited by:

    1. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study," IJERPH, MDPI, vol. 19(13), pages 1-27, June.

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