In aggregate, our data suggest a model of SCLC pathogenesis in never-smokers involving two distinct plasticity-mediated pathways (Fig. 6F)—one, known from prior studies but expanded in our cohort, with a histogenetic link to NSCLC precursors, where conversion to SCLC occurs in RB1−/TP53− background in association with APOBEC mutagenesis, and the other, a novel pathway, with a histogenetic link to carcinoid precursors, where the plasticity occurs in an RB1+/TP53+ background through chromothripsis-mediated amplification of oncogenes, some of which have key roles in pRb and p53 suppression. Here, TP53 is linked to non-small cell lung carcinoma.