Clonal history of small cell carcinomas transformed from lung adenocarcinomas

Abstract

It has been regarded that each histologic subtype of lung cancer originates from different type of normal cells in the airway. However, recent clinical observations on patients whose EGFR-mutant lung adenocarcinomas underwent histologic transformation into small cell carcinomas during EGFR tyrosine kinase inhibitor treatments indicated there could be exceptions. These cases have clinical implication because small-cell transformation results in resistance to EGFR inhibition, frequently leading to a rapid deterioration of patient's clinical course. Although transformation of small cell lung cancer could account for 4 to 14 percent of acquired resistance cases toward EGFR tyrosine kinase inhibitors, the molecular pathogenesis of this phenomenon remains elusive. To explore the biological process underlying this phenomenon especially in terms of clonal evolution, here I investigated EGFR inhibitor-resistant, transformed small cell lung cancer cases. From a patient cohort of advanced EGFR-mutant lung adenocarcinomas (n = 136), nine (7%) patients were identified as whose tumor was histologically transformed into small cell lung cancer at the point of resistance to EGFR inhibitors. Using whole-genome sequencing, I found that EGFR tyrosine kinase inhibitor-resistant lung adenocarcinomas and small cell lung cancers shared common clonal origin and underwent branched evolutionary trajectories. The clonal divergence of ancestral cells of small cell lung cancers from the lung adenocarcinoma cells occurred even before the first EGFR inhibitor treatments, and the common ancestor cells had complete inactivation of both RB1 and TP53, which was unusual for ordinary lung adenocarcinomas. Branch-specific mutational signature analysis revealed that APOBEC-induced hypermutation preferentially occurred in the branches toward small-cell transformation, and could account for a majority (~56%) of new mutations in these branches. This study indicates that EGFR tyrosine kinase inhibitor-resistant small cell lung cancers originate from the lung adenocarcinoma clones harboring completely inactivated RB1 and TP53 through branched evolutionary trajectory, frequently accompanying APOBEC-induced hypermutation.