Synapse - Chromothripsis-mediated small cell lung carcinoma

Chromothripsis-mediated small cell lung carcinoma Journal Article

Authors:	Rekhtman, N.; Tischfield, S. E.; Febres-Aldana, C. A.; Lee, J. J. K.; Chang, J. C.; Herzberg, B. O.; Selenica, P.; Woo, H. J.; Vanderbilt, C. M.; Yang, S. R.; Xu, F.; Bowman, A. S.; da Silva, E. M.; Noronha, A. M.; Mandelker, D. L.; Mehine, M.; Mukherjee, S.; Blanco-Heredia, J.; Orgera, J. J.; Nanjangud, G. J.; Baine, M. K.; Aly, R. G.; Sauter, J. L.; Travis, W. D.; Savari, O.; Moreira, A. L.; Falcon, C. J.; Bodd, F. M.; Wilson, C. E.; Sienty, J. V.; Manoj, P.; Sridhar, H.; Wang, L.; Choudhury, N. J.; Offin, M.; Yu, H. A.; Quintanal-Villalonga, A.; Berger, M. F.; Ladanyi, M.; Donoghue, M. T. A.; Reis-Filho, J. S.; Rudin, C. M.
Article Title:	Chromothripsis-mediated small cell lung carcinoma
Abstract:	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. © 2024 The Authors; Published by the American Association for Cancer Research.
Keywords:	aged; middle aged; genetics; ubiquitin protein ligase; lung neoplasms; pathology; protein p53; lung tumor; tumor suppressor protein p53; tp53 protein, human; ubiquitin-protein ligases; small cell lung cancer; small cell lung carcinoma; retinoblastoma binding protein; chromothripsis; humans; human; male; female; rb1 protein, human; retinoblastoma binding proteins
Journal Title:	Cancer Discovery
Volume:	15
Issue:	1
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2025-01-01
Start Page:	83
End Page:	104
Language:	English
DOI:	10.1158/2159-8290.Cd-24-0286
PUBMED:	39185963
PROVIDER:	scopus
PMCID:	PMC11726019
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85215647565&doi=10.1158%2f2159-8290.CD-24-0286&partnerID=40&md5=bcc35a902328b16d25d029930870a53c
Notes:	Article -- MSK corresponding authors are Charles Rudin and Natasha Rekhtman -- Source: Scopus