Next-generation Sequencing Reveals Age-dependent Genetic Underpinnings in Lung adenocarcinoma.

: More than 40% of lung cancer patients are diagnosed at ages over 70. However, the genomic and clinical characteristics among them remain elusive. Here, we performed targeted capture sequence to characterize the mutational spectrum of Chinese lung adenocarcinoma (LUAD) patients across ages. : 2025 LUAD patients were divided into three groups: young (≤50 years old) (n=416, 20.54%), intermediate (51~69 years old) (n=1271, 62.77%), and aged (≥70 years old) (n=338, 16.69%). 1,021-gene panel and 59-gene panel were used for sequencing with tissue samples. Genetic alterations and tumor mutation burden (TMB) in LUAD patients were investigated. : The frequency of mutations affecting 20 genes were significantly higher in aged group than in young group, and fourteen of them were not reported before, including involved in cell cycle/apoptosis signaling (), DNA damage repair ( and ), chromatin histone modification (), signaling ( and ), signaling ( and ) and other signaling pathway or cellular regulatory factor ( and ). Six previously reported mutated genes (, , , and ) were also significantly more frequent in aged group. Among clinical actionable mutation sites, mutation was presented more common in aged group; both exon 14 skipping and amplification were significantly positively correlated with old age; the fusions of , exon 20 insertion were less frequent in aged group. Furthermore, a higher level of TMB was found in aged group compared with young group. In this study, we revealed the differences of somatic genetic mutations and TMB between young and aged LUAD patients, which may provide directions of targeted therapy and advantages of immunotherapy for the elderly in the future.