New subtypes of high-grade neuroendocrine tumours revealed

Large-cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive form of lung cancer. Confusingly, LCNEC has molecular and pathological features in common with not only neuroendocrine small-cell lung cancers (SCLCs) but also adenocarcinomas and squamous cell carcinomas, and can sometimes co-occur with any of these other cancer types. Now, comprehensive integrative genomic and transcriptomic profiling of 75 LCNECs has revealed two molecular subgroups: type I LCNECs, characterized by biallelic TP53 and STK11 and/or KEAP1 alterations, and a neuroendocrine differentiation phenotype (ASLC1^highDLL3^highNOTCH^low); and type II tumours, which have biallelic inactivation of TP53 but also RB1, are ASLC1^lowDLL3^lowNOTCH^high, and have upregulation of immune-related pathways. These findings have implications for clinical trials: patients with type I LCNECs might be candidates for DLL3-directed therapies that have promising activity against SCLC, whereas those with type II LCNECs might respond to Notch-targeted agents or immunotherapy.