Chromothripsis in small cell lung carcinoma associated with carcinoid transformation

Small cell lung carcinoma (SCLC) is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. We performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC in never/light smokers that lacked RB1 and TP53 co-inactivation and found that most cases were associated with chromothripsis _ massive, localized chromosome shattering, recurrently involving chromosomes 11 or 12, among other findings. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids. Conversely, SCLC 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.