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Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Author

Listed:
  • Amin H. Nassar

    (Yale School of Medicine and Yale Cancer Center)

  • Chul Kim

    (Georgetown Cancer Institute)

  • Tolulope Adeyelu

    (Caris Life Sciences)

  • Elias Bou Farhat

    (Brigham and Women’s Hospital)

  • Hassan Abushukair

    (University of Oklahoma Health Sciences Center
    University of Oklahoma Health Sciences Center)

  • Mehrdad Rakaee

    (Brigham and Women’s Hospital
    Oslo University Hospital)

  • Kelsey Matteson

    (Yale School of Medicine and Yale Cancer Center)

  • Shun-Fat Lau

    (Yale University)

  • Yamato Takabe

    (Yale University)

  • Antonio Ocejo

    (Jackson Memorial Hospital)

  • Fatemeh Ardeshir-Larijani

    (Winship Cancer Institute of Emory University)

  • Ticiana Leal

    (Winship Cancer Institute of Emory University)

  • Suresh Ramalingam

    (Winship Cancer Institute of Emory University)

  • Sumaiya Alam

    (Winship Cancer Institute of Emory University)

  • Jhanelle E. Gray

    (Moffitt Cancer Center)

  • James Hicks

    (Moffitt Cancer Center)

  • David Kaldas

    (Moffitt Cancer Center)

  • Javier Baena

    (Hospital 12 de Octubre)

  • Maria Zurera Berjaga

    (Hospital 12 de Octubre)

  • Frank Aboubakar Nana

    (Cliniques Universitaires Saint Luc)

  • Christian Grohe

    (Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch)

  • Heike Leuders

    (Klinik für Pneumologie-Evangelische Lungenklinik, Berlin Buch)

  • Fabrizio Citarella

    (Università Campus Bio-Medico di Roma)

  • Alessio Cortellini

    (Università Campus Bio-Medico di Roma
    Fondazione Policlinico Universitario Campus Bio-Medico
    Hammersmith Hospital)

  • Emanuele Claudio Mingo

    (Università Campus Bio-Medico di Roma)

  • Danny Pancirer

    (Stanford Cancer Institute)

  • Millie Das

    (Stanford Cancer Institute
    VA Palo Alto Health Care System)

  • Timothy John Ellis-Caleo

    (Stanford Cancer Institute)

  • Justin M. Cheung

    (Massachusetts General Hospital)

  • Jessica J. Lin

    (Massachusetts General Hospital)

  • Alexander S. Watson

    (University of Colorado Cancer Center)

  • D. Ross Camidge

    (University of Colorado Cancer Center)

  • Arthi Sridhar

    (Mayo Clinic)

  • Kaushal Parikh

    (Mayo Clinic)

  • Fionnuala Crowley

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Thomas U. Marron

    (Icahn School of Medicine at Mount Sinai)

  • Vanya Aggarwal

    (Georgetown Cancer Institute)

  • Murtaza Ahmed

    (Cedars Sinai Medical Center)

  • Kamya Sankar

    (Cedars Sinai Medical Center)

  • Hassan Kawtharany

    (University of Kansas Medical Center)

  • Jun Zhang

    (University of Kansas Medical Center)

  • Dwight H. Owen

    (The Ohio State University Comprehensive Cancer Center)

  • Mingjia Li

    (The Ohio State University Comprehensive Cancer Center)

  • Misako Nagasaka

    (UC Irvine)

  • David J. Pinato

    (Hammersmith Hospital
    University of Piemonte Orientale)

  • Nichola Awosika

    (Hammersmith Hospital)

  • Khaled Alhamad

    (Huntsman Cancer Institute)

  • Sonam Puri

    (Huntsman Cancer Institute)

  • Unaiza Zaman

    (University of Oklahoma Health Sciences Center)

  • Divya M. Gupta

    (Northwestern University)

  • Chelsea Lau

    (Northwestern University)

  • Hina Khan

    (The Warren Alpert Medical School of Brown University)

  • Justin Liauw

    (The Warren Alpert Medical School of Brown University)

  • Ana I. Velazquez

    (University of California San Francisco Helen Diller Family Comprehensive Cancer Center)

  • Tyiesha Brown

    (University of California San Francisco Helen Diller Family Comprehensive Cancer Center)

  • Laura Moliner

    (L’Hospitalet de Llobregat)

  • Miguel Mosteiro

    (L’Hospitalet de Llobregat)

  • Pedro Rocha

    (Vall d’Hebron University Hospital)

  • Mark Evans

    (Caris Life Sciences)

  • Ari Vanderwalde

    (Caris Life Sciences)

  • Andrew Elliott

    (Caris Life Sciences)

  • Jorge Nieva

    (University of Southern California)

  • Gilberto Lopes

    (Jackson Memorial Hospital)

  • Patrick C. Ma

    (Penn State University)

  • Hossein Borghaei

    (Fox Chase Cancer Center)

  • Matthew Lee

    (Montefiore Medical Center/Albert Einstein College of Medicine)

  • Lauren Young

    (Montefiore Medical Center/Albert Einstein College of Medicine)

  • Raid Aljumaily

    (University of Oklahoma Health Sciences Center)

  • Haris Mirza

    (Yale School of Medicine)

  • David J. Kwiatkowski

    (Brigham and Women’s Hospital)

  • Roy S. Herbst

    (Yale School of Medicine and Yale Cancer Center)

  • Richard A. Flavell

    (Yale University)

  • Abdul Rafeh Naqash

    (University of Oklahoma Health Sciences Center)

  • Anne C. Chiang

    (Yale School of Medicine and Yale Cancer Center)

Abstract

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling reveals stable mutational but shifting transcriptomic landscapes over time. Here we show, elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression in NSCLC-like LCNECs, and higher levels of DLL3 in SCLC-like LCNECs. Immunofluorescence confirms FGL-1 expression in NSCLC-like LCNECs, and H&E slide analyses indicates fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Suggested Citation

  • Amin H. Nassar & Chul Kim & Tolulope Adeyelu & Elias Bou Farhat & Hassan Abushukair & Mehrdad Rakaee & Kelsey Matteson & Shun-Fat Lau & Yamato Takabe & Antonio Ocejo & Fatemeh Ardeshir-Larijani & Tici, 2025. "Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63091-0
    DOI: 10.1038/s41467-025-63091-0
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