IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-03099-x.html
   My bibliography  Save this article

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

Author

Listed:
  • Julie George

    (University of Cologne)

  • Vonn Walter

    (University of North Carolina at Chapel Hill
    500 University Drive)

  • Martin Peifer

    (University of Cologne
    University of Cologne)

  • Ludmil B. Alexandrov

    (University of California)

  • Danila Seidel

    (University of Cologne)

  • Frauke Leenders

    (University of Cologne)

  • Lukas Maas

    (University of Cologne)

  • Christian Müller

    (University of Cologne)

  • Ilona Dahmen

    (University of Cologne)

  • Tiffany M. Delhomme

    (International Agency for Research on Cancer (IARC-WHO))

  • Maude Ardin

    (International Agency for Research on Cancer (IARC-WHO))

  • Noemie Leblay

    (International Agency for Research on Cancer (IARC-WHO))

  • Graham Byrnes

    (International Agency for Research on Cancer (IARC-WHO))

  • Ruping Sun

    (Max Planck Institute for Molecular Genetics)

  • Aurélien Reynies

    (Ligue Nationale Contre le Cancer)

  • Anne McLeer-Florin

    (CHU Grenoble Alpes, UGA/INSERM U1209/CNRS)

  • Graziella Bosco

    (University of Cologne)

  • Florian Malchers

    (University of Cologne)

  • Roopika Menon

    (NEO New Oncology GmbH)

  • Janine Altmüller

    (University of Cologne
    University of Cologne
    University Hospital Cologne)

  • Christian Becker

    (University of Cologne)

  • Peter Nürnberg

    (University of Cologne
    University of Cologne
    University of Cologne)

  • Viktor Achter

    (University of Cologne)

  • Ulrich Lang

    (University of Cologne
    University of Cologne)

  • Peter M. Schneider

    (University Hospital Cologne)

  • Magdalena Bogus

    (University Hospital Cologne)

  • Matthew G. Soloway

    (University of North Carolina at Chapel Hill)

  • Matthew D. Wilkerson

    (The University of North Carolina at Chapel Hill)

  • Yupeng Cun

    (University of Cologne
    University of Cologne)

  • James D. McKay

    (International Agency for Research on Cancer (IARC-WHO))

  • Denis Moro-Sibilot

    (University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043)

  • Christian G. Brambilla

    (University Grenoble Alpes, Institute of Advanced Biosciences (IAB), 38043)

  • Sylvie Lantuejoul

    (University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043
    Centre Léon Bérard UNICANCER)

  • Nicolas Lemaitre

    (University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043)

  • Alex Soltermann

    (University Hospital Zurich)

  • Walter Weder

    (University Hospital Zurich)

  • Verena Tischler

    (University Hospital Zurich)

  • Odd Terje Brustugun

    (University of Oslo
    Oslo University Hospital)

  • Marius Lund-Iversen

    (Oslo University Hospital)

  • Åslaug Helland

    (University Hospital Zurich
    University of Oslo)

  • Steinar Solberg

    (Oslo University Hospital)

  • Sascha Ansén

    (University Hospital Cologne)

  • Gavin Wright

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

  • Benjamin Solomon

    (Peter MacCallum Cancer Centre)

  • Luca Roz

    (Fondazione IRCCS—Istituto Nazionale Tumori)

  • Ugo Pastorino

    (Fondazione IRCCS Istituto Nazionale Tumori)

  • Iver Petersen

    (Friedrich-Schiller-University)

  • Joachim H. Clement

    (Friedrich-Schiller-University)

  • Jörg Sänger

    (Institute for Pathology Bad Berka)

  • Jürgen Wolf

    (University Hospital Cologne)

  • Martin Vingron

    (Max Planck Institute for Molecular Genetics)

  • Thomas Zander

    (University Hospital of Cologne
    University Hospital Cologne)

  • Sven Perner

    (Leibniz Center for Medicine and Biosciences)

  • William D. Travis

    (Memorial Sloan-Kettering Cancer Center)

  • Stefan A. Haas

    (Max Planck Institute for Molecular Genetics)

  • Magali Olivier

    (International Agency for Research on Cancer (IARC-WHO))

  • Matthieu Foll

    (International Agency for Research on Cancer (IARC-WHO))

  • Reinhard Büttner

    (University Hospital Cologne)

  • David Neil Hayes

    (University of North Carolina at Chapel Hill)

  • Elisabeth Brambilla

    (University of Grenobles Alpes, Institute of Advanced Biosciences (IAB), 38043)

  • Lynnette Fernandez-Cuesta

    (University of Cologne
    International Agency for Research on Cancer (IARC-WHO))

  • Roman K. Thomas

    (University of Cologne
    University Hospital Cologne
    German Cancer Consortium (DKTK))

Abstract

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Suggested Citation

  • Julie George & Vonn Walter & Martin Peifer & Ludmil B. Alexandrov & Danila Seidel & Frauke Leenders & Lukas Maas & Christian Müller & Ilona Dahmen & Tiffany M. Delhomme & Maude Ardin & Noemie Leblay &, 2018. "Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03099-x
    DOI: 10.1038/s41467-018-03099-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-03099-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-03099-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03099-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.