Chromothripsis-Mediated Small Cell Lung Carcinoma
Menée à l'aide de données clinicopathologiques portant sur des patients atteints d'un carcinome du poumon à petites cellules et menée à partir de l'analyse génomique et transcriptomique d'échantillons tumoraux, cette étude met en évidence le rôle du phénomène de chromothripsie dans le développement d'un sous-type rare de carcinome pulmonaire à petites cellules se caractérisant par l'absence d'inactivation concomitante de RB1 et de TP53, sa survenue chez les non-fumeurs ou fumeurs légers et ses liens histogénétiques avec les tumeurs carcinoïdes de bas grade
Résumé en anglais
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.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.
