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.]]>

小细胞肺癌（Small cell lung carcinoma, SCLC）通常与烟草暴露以及RB1、TP53基因失活相关。本研究对从不吸烟者/轻度吸烟者中的非典型小细胞肺癌亚群开展了详细的临床病理、基因组及转录组分析，该亚群未出现RB1与TP53的共失活；研究发现多数病例伴随染色体碎裂（chromothripsis）——即大规模局灶性染色体破碎，且反复累及11号或12号染色体等特征。尤为特殊的是，这类具有临床侵袭性的肿瘤在基因组与病理特征上与肺类癌存在关联。与之相对，携带RB1与TP53失活的从不吸烟者小细胞肺癌患者呈现出腺癌向小细胞肺癌转化的典型特征，这为从不吸烟者群体中小细胞肺癌通过两种截然不同的可塑性介导发病机制发生提供了佐证。