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

Journal Article · · Nature Communications
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  1. Univ. of Cologne (Germany)
  2. Univ. of North Carolina, Chapel Hill, NC (United States); Penn State Milton S. Hershey Medical Center, Hershey, PA (United States)
  3. Univ. of California, San Diego, CA (United States)
  4. International Agency for Research on Cancer (IARC-WHO), Lyon (France)
  5. Max Planck Inst. for Molecular Genetics, Berlin (Germany)
  6. Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer Paris (France)
  7. Centre Hospitalier Universitaire (CHU) de Grenoble, Genoble (France)
  8. NEO New Oncology GmbH, Cologne (Germany)
  9. Univ. of Cologne (Germany); University Hospital Cologne, Cologne (Germany)
  10. University Hospital Cologne, Cologne (Germany)
  11. Univ. of North Carolina, Chapel Hill, NC (United States)
  12. Univ. de Grenoble Alpes, Grenoble (France)
  13. Univ. de Grenoble Alpes, Grenoble (France); Centre Leon Berard UNICANCER, Lyon (France)
  14. Univ. Hospital Zurich, Zurich (Switzerland)
  15. Univ. of Oslo (Norway); Oslo Univ. Hospital, Oslo (Norway)
  16. Oslo Univ. Hospital, Oslo (Norway)
  17. St. Vincent’s Hospital, Melbourne, VIC (Australia)
  18. Peter MacCallum Cancer Centre, Melbourne, VIC (Australia)
  19. Fondazione IRCCS-Istituto Nazionale Tumori, Milan (Italy)
  20. Friedrich Schiller Univ., Jena (Germany)
  21. Institute for Pathology Bad Berka, Bad Berka (Germany)
  22. Max Planck Inst. for Molecular Genetics, Berlin(Germany)
  23. Univ. Medical Center Schleswig-Holstein, Luebeck, Borstel (Germany)
  24. Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
  25. Univ. of Cologne (Germany); International Agency for Research on Cancer (IARC-WHO), Lyon (France)
  26. Univ. of Cologne (Germany); University Hospital Cologne, Cologne (Germany); German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg (Germany)
+ Show Author Affiliations

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here in this paper 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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Laboratory Directed Research and Development (LDRD) Program
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1460632
Report Number(s):
LA-UR-16-29056
Journal Information:
Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 186 works
Citation information provided by
Web of Science

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Cited By (21)

iRODS metadata management for a cancer genome analysis workflow text January 2019
Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data journal March 2019
Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens? journal January 2019
Tumor Heterogeneity Underlies Differential Cisplatin Sensitivity in Mouse Models of Small-Cell Lung Cancer journal June 2019
Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids journal August 2019
DLL3: an emerging target in small cell lung cancer journal June 2019
Are neuroendocrine negative small cell lung cancer and large cell neuroendocrine carcinoma with WT RB1 two faces of the same entity? journal October 2019
Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature journal January 2020
Multiregion Comprehensive Genomic Profiling of a Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm with Trilineage Differentiation journal January 2018
Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells journal July 2018
Ion beam analysis of fusion plasma-facing materials and components: facilities and research challenges journal December 2019
Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype journal December 2019
A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal journal August 2018
iRODS metadata management for a cancer genome analysis workflow journal January 2019
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Neuroendocrine marker staining pattern categorization of small‐sized pulmonary large cell neuroendocrine carcinoma journal September 2019
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Differential development of large-cell neuroendocrine or small-cell lung carcinoma upon inactivation of 4 tumor suppressor genes journal October 2019
“Keaping” a lid on lung cancer: the Keap1-Nrf2 pathway journal July 2018

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