Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD)

BACKGROUND: Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non- EGFR: mutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined. METHODS: Whole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC. RESULTS: After SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs. 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC. CONCLUSIONS: The transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.