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.

This content is only available via PDF.
©2024 The Authors; Published by the American Association for Cancer Research
2024
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
This work is licensed under a Creative Commons Attribution 4.0 International License .
Attribution

Article PDF first page preview

Article PDF first page preview

Supplementary data

Supplementary Tables S1-S13

Supplementary Table S1. Integrated genomic and immunohistochemical results for TP53 and RB1 in aSCLC Supplementary Table S2. Demographic, clinicopathologic and immunohistochemical characteristics: Per patient data Supplementary Table S3. Samples and studies performed: Per sample data Supplementary Table S4. Clinicopathologic comparison aSCLC vs other SCLC Supplementary Table S5. MSK-IMPACT metrics and full results for all samples Supplementary Table S6. Full list of SNV by MSK-IMPACT in aSCLC Supplementary Table S7. Full list of CNA by MSK-IMPACT in aSCLC Supplementary Table S8. RB1 and TP53 non-coding variant annotation by WGS Supplementary Table S9. Full list of SV by WGS in aSCLC Supplementary Table S10. Full list of fusions by RNAseq in aSCLC Supplementary Table S11. Timing of amplifications by WGS: mutTimerR Supplementary Table S12. Immunohistochemical antibodies, protocols and scoring criteria Supplementary Table S13. List of covered genes by targeted NGS (MSK-IMPACT assay): somatic and germline.

- xlsx file
Supplementary Figures S1-S13

Supplementary Figure S1. Detailed morphologic and immunohistochemical findings: Case A01. Supplementary Figure S2. Detailed morphologic and immunohistochemical findings: Case A08. Supplementary Figure S3. Detailed morphologic and immunohistochemical findings: Case A17. Supplementary Figure S4. Detailed morphologic and immunohistochemical findings: Case A20. Supplementary Figure S5. Mutational signatures in atypical SCLC (aSCLC), never-smoker SCLC with RB1–/TP53– (nsSCLC) and smoking-associated SCLC (sSCLC) analyzed by MSK-IMPACT. Supplementary Figure S6. Circos plots showing structural variants and copy number alterations across the genome from all cases with WGS. Supplementary Figure S7. Chromothripsis assessment by targeted NGS (MSK-IMPACT) versus WGS. Supplementary Figure S8. RNAseq for non-recurrently amplified (KRAS, ERBB3, KDM5A) or deleted (TGFBR2, ARID1A) genes on chromothriptic chromosomes and TERT. Supplementary Figure S9. Comparison of chromothripsis characteristics in aSCLC vs other major lung cancer types. Supplementary Figure S10. Chromothripsis architecture in all cases profiled by whole-genome sequencing. Supplementary Figure S11. Chromothripsis in multi-sample analysis and genomic alterations in samples with histotype heterogeneity. Supplementary Figure S12. Cell cycle and p53 pathway deregulation in aSCLC. Supplementary Figure S13. Expression of potential therapeutic markers in aSCLC.

- pdf file