Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma

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...

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Main Authors: 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, Ticiana Leal, Suresh Ramalingam, Sumaiya Alam, Jhanelle E. Gray, James Hicks, David Kaldas, Javier Baena, Maria Zurera Berjaga, Frank Aboubakar Nana, Christian Grohe, Heike Leuders, Fabrizio Citarella, Alessio Cortellini, Emanuele Claudio Mingo, Danny Pancirer, Millie Das, Timothy John Ellis-Caleo, Justin M. Cheung, Jessica J. Lin, Alexander S. Watson, D. Ross Camidge, Arthi Sridhar, Kaushal Parikh, Fionnuala Crowley, Thomas U. Marron, Vanya Aggarwal, Murtaza Ahmed, Kamya Sankar, Hassan Kawtharany, Jun Zhang, Dwight H. Owen, Mingjia Li, Misako Nagasaka, David J. Pinato, Nichola Awosika, Khaled Alhamad, Sonam Puri, Unaiza Zaman, Divya M. Gupta, Chelsea Lau, Hina Khan, Justin Liauw, Ana I. Velazquez, Tyiesha Brown, Laura Moliner, Miguel Mosteiro, Pedro Rocha, Mark Evans, Ari Vanderwalde, Andrew Elliott, Jorge Nieva, Gilberto Lopes, Patrick C. Ma, Hossein Borghaei, Matthew Lee, Lauren Young, Raid Aljumaily, Haris Mirza, David J. Kwiatkowski, Roy S. Herbst, Richard A. Flavell, Abdul Rafeh Naqash, Anne C. Chiang
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-63091-0
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Summary: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.
ISSN:2041-1723

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