Aging-related transcriptomic signatures associated with recurrence following resection of stage I lung adenocarcinoma

Abstract

Age is an independent prognostic factor in early-stage non-small cell lung cancer, yet age-associated molecular differences and their association with cancer recurrence remain poorly understood. We investigated transcriptomic differences associated with aging and recurrence in stage I lung adenocarcinoma (LUAD). Bulk RNA sequencing was performed on tumor and adjacent normal lung tissue (NAT) from 126 patients with resected stage I LUAD. Differential expression, pathway enrichment, and multiscale embedded gene co-expression network analysis (MEGENA) were used to identify age- and recurrence-associated transcriptional differences. External confirmation was performed using TCGA and TRACERx cohorts. Older patients ( > 70 years) with recurrence demonstrated marked upregulation of cancer-associated, inflammatory, and extracellular matrix (ECM) pathways in tumors compared with older patients without recurrence. In NAT samples, older patients with recurrence showed upregulation of inflammatory and immune-related pathways, including IL-17, IL-6, and Th2 signaling, whereas these pathways were absent or downregulated in younger patients. MEGENA identified a larger number of recurrence-associated co-expression modules in older versus younger patients. These findings were partially supported in external cohorts, particularly in tumor tissue. Our findings suggest that aging in LUAD is associated with distinct inflammatory and cancer-related transcriptomic alterations associated with recurrence.