Comparison of genomic landscapes of large cell neuroendocrine carcinoma, small cell lung carcinoma, and large cell carcinoma

BACKGROUND: The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. METHODS: We performed capture‐based ultra‐deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. RESULTS: Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. CONCLUSION: Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events.