Abstract
Early-onset lung cancer in young adults represents a less studied clinical entity with increasing incidence which still affects a large number of cancer patients. Here we perform a comprehensive analysis of early-onset lung cancer for the clinicopathological features, genomic alterations, gene expression, and immune landscape by establishing a cohort enrolling 421 non-small cell lung cancer (NSCLC) patients from ten medical centers in China. Comparative analysis reveals a distinct genomic alteration between younger and elder patients with NSCLC, with ERBB2 mutations and ALK-rearrangement strikingly more frequent in younger group. Transcriptome profiling indicates altered cellular metabolism and immune-related genes in tumors from younger patients. Immunological analysis reveals a decreased infiltration of immune cells (notably T cells) in tumors from younger patients. Cellular and mechanistic studies show that the prevalent ERBB2 mutants in cancer from younger patients can indeed drive tumorigenesis by elevating AKT signaling. Importantly, meta-analysis of clinical trials and our clinical practice further validate the promise of HER2-targeted therapy to treat early-onset NSCLC in East Asian patients. Our comprehensive and integrative analysis not only reveal multiple unrecognized characteristics of early-onset lung cancer, but also inform actionable therapeutics to manage this type of cancer.