Chromothripsis-Mediated Small Cell Lung Carcinoma

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.

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Publication Details

Journal
Cancer Discovery
Published
2024-08-26
DOI
https://doi.org/10.1158/2159-8290.cd-24-0286
Citations
39
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
11.02

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article

Chromothripsis-Mediated Small Cell Lung Carcinoma

Christina J. Falcon, Harsha Sridhar, Michael David Offin, Francis M. Bodd et al.
39 citations
Cancer Discovery
Lung Cancer Research Studies
11.02
article

Chromothripsis-Mediated Small Cell Lung Carcinoma

Christina J. Falcon, Harsha Sridhar, Michael David Offin, Francis M. Bodd, Juan Blanco-Heredia, Anne Marie Noronha, Pier Selenica, Helena A. Yu, Omid Savari, Benjamin Herzberg, Noura J. Choudhury, Àlvaro Quintanal-Villalonga, Michael F. Berger, Mark T.A. Donoghue, André L. Moreira, Rania G. Aly, Miika M. Mehine, William D. Travis, Edaise M. da Silva, Marc Ladanyi, Gouri J. Nanjangud, Charles M. Rudin, Jake June-Koo Lee, Marina K. Baine, Jason C. Chang, Parvathy Manoj, Jennifer L. Sauter, Diana L. Mandelker, Soo‐Ryum Yang, Anita S. Bowman, John J. Orgera, Jorge S. Reis‐Filho, Sam E. Tischfield, Natasha Rekhtman, Semanti Mukherjee, Chad Vanderbilt, Lu Wang, Fei Xu, Hyung Jun Woo, Christina E. Wilson, Jacklynn V. Sienty, Christopher A. Febres‐Aldana
article en
39 citations

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. See related commentary by Nadeem and Drapkin, p. 8.

Cancer DiscoveryVol. 15(1)
St. Jude Children's Research Hospital (US), Memorial Sloan Kettering Cancer Center (US), Cornell University (US), University Hospitals of Cleveland (US), Columbia University Irving Medical Center (US), Cancer Research And Biostatistics (US), AstraZeneca (United States) (US), New York University (US)
Mesothelioma Applied Research Foundation, LUNGevity Foundation, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Vanderbilt University, Novocure, G1 Therapeutics, Astellas Pharma, National Institutes of Health, Genentech, Loxo Oncology, National Cancer Institute, Janssen Pharmaceuticals
Good health and well-being
Openalex Percentile: Top 1%
Lung Cancer Research Studies
11.02
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