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 chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) 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.

中文翻译：

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染色体碎裂介导的小细胞肺癌


小细胞肺癌 (SCLC) 是一种高度侵袭性的恶性肿瘤，通常与烟草接触以及 RB1 和 TP53 基因失活有关。在这里，我们对 SCLC 的非典型子集进行了详细的临床病理学、基因组和转录组学分析，该子集缺乏 RB1 和 TP53 共失活，并且出现在从不吸烟/轻度吸烟者中。我们发现大多数病例与染色体碎裂（大规模、局部染色体破碎）有关，反复涉及 11 号或 12 号染色体，并分别导致 CCND1 的染色体外 (ecDNA) 扩增或 CCND2/CDK4/MDM2 的共扩增。独特的是，这些临床侵袭性肿瘤表现出与肺类癌的基因组和病理学联系，表明 SCLC 发病机制是一种以前未知的模式，是通过低级别神经内分泌肿瘤或其祖细胞的转化而实现的。相反，携带失活 RB1 和 TP53 的从不吸烟者中的 SCLC 表现出腺癌到 SCLC 衍生的标志，支持从不吸烟者中可塑性介导的 SCLC 发病机制的两种不同途径。