Cancer discoveryJournal Article
13 Jan 2025
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes.
Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers.
We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively.
Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors.
Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.
Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features.
This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8.
N. Rekhtman reports serving on the scientific advisory board of Merck. B.O. Herezberg reports consulting and receiving personal fees from Amgen, Astellas, Eli Lilly and Company, Boxer Capital, MJH Life Sciences, Guardant Health, and IDEOlogy Health outside the current work, as well as received grants from AZ. C.M. Vanderbilt reports equity, intellectual property rights, professional services, and activities (uncompensated) from Paige.AI, Inc. S.-R. Yang reports uncompensated professional services and activities from Genentech. D.L. Mandelker reports consulting fees from AstraZeneca. W.D. Travis reports uncompensated professional services and activities from Genentech. A.L. Moreira reports a grant from Bristol Myers and Squibb outside the scope of this work. N.J. Choudhury reports research funding from the following: AbbVie, Amgen, Harpoon Therapeutics, Merck, Monte Rosa Therapeutics, Roche/Genentech, as well as serving on the scientific advisory board of Harpoon Therapeutics and AbbVie and receiving honoraria from G1 Therapeutics and Sanofi, and receiving royalties from Wolters Kluwer, all of which are outside the scope of the submitted work. M. Offin reports consulting roles/honorarium with Novartis, Jazz, Pfizer, Targeted Oncology, OncLive, and American Society for Radiation Oncology and grant support from the Druckenmiller Foundation and LUNGevity Foundation, as well as being an uncompensated scientific advisory board member for the Mesothelioma Applied Research Foundation. H.A. Yu reports grants from the NIH/NCI during the conduct of this study, as well as personal fees from AstraZeneca, Daiichi, Janssen, AbbVie, Amgen, Novocure, Black Diamond, Taiho, Takeda, and Cullinan outside of the scope of this project. A. Quintanal-Villalonga reports receiving honoraria from AstraZeneca. M.F. Berger reports personal fees from Eli Lilly and Company, AstraZeneca and Paige.AI, as well as research support from Boundless Bio and intellectual property rights from SOPHiA Genetics. M. Ladanyi reports receiving honoraria for advisory board participation from Merck, AstraZeneca, Bristol Myers and Squibb, Blueprint Medicines, Janssen Pharmaceuticals, Takeda Pharmaceuticals, Lilly Oncology, Loxo Oncology, Bayer, ADC Therapeutics, Riken Genesis/Sysmex, and PaigeAI, as well as research support from Rain Oncology, Loxo Oncology, Merus, Elevation Oncology, Helsinn Therapeutics, and ADC Therapeutics. J.S. Reis-Filho reports employment at AstraZeneca. C.M. Rudin reports serving as consultant for Amgen, AstraZeneca, Chugai, D2G, Daiichi Sankyo, Hoffman-La Roche, Jazz, and Legend, as well as serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. No disclosures were reported by the other authors.
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