Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma
(2025) Nature Communications — Vol. 16, n° 1 (2025)
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Nassar, Amin H. 
Bou Farhat, Elias Chiang, Anne C.
- 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 immunogenomicprofile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.
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Nassar, A. H., Kim, C., Adeyelu, T., Bou Farhat, E., Abushukair, H., Rakaee, M., Matteson, K., Lau, S.-F., Takabe, Y., Ocejo, A., Ardeshir-Larijani, F., Leal, T., Ramalingam, S., Alam, S., Gray, J. E., Hicks, J., Kaldas, D., Baena, J., Berjaga, M. Z., et al. (2025). Integrated molecular and clinical characterization of pulmonary large cell neuroendocrine carcinoma. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-63091-0 (Original work published 2025)