Distinct Molecular Features In Early-onset Lung Adenocarcinoma

Objective: Early-onset non-small cell lung cancer(NSCLC)in young patients accounts for 1-10% incidence of lung cancer.The molecular characteristics of this subtype remain poorly understood.Method: We conducted a cohort study enrolling 101 patients with lung adenocarcinoma from Department of Thoracic Surgery of The Fourth Affiliated Hospital of China Medical University to compare early-onset lung adenocarcinoma in young patients with late-onset disease in elder counterparts.Mutational profiles of 16 targetable driver genes were determined in the cohort.RNA sequencing and immunohistochemistry analysis were performed to further characterize the molecular features at levels of gene expression and tumor immune microenvironment.Results: EGFR,ERBB2,ALK and TP53 were the top four mutated genes of all the young patients in the cohort.ERBB2 and ALK mutations were significantly more frequent in early-onset than late-onset lung adenocarcinoma.Genes differentially expressed in young patients versus elder counterparts were enriched in tumor signaling pathways(including RAS,p53 and PPAR signaling),tumor immune microenvironment and metabolic processes.Furthermore,immunohistochemistry analysis revealed decreased tumor immune cell infiltration(e.g.,CD4,CD8,and CD3 positive T lymphocytes)in tumors from young patients.Conclusions: Our integrative analysis from multiple perspectives reveals distinct molecular features in early-onset lung adenocarcinoma,which not only helps to understand the molecular basis behind this malignancy subtype,but also suggests potential biomarkers and targeted therapies such as HER2-targeting drugs for the clinical management of young adults with NSCLC.