Abstract
Spread through air spaces (STAS) is an adverse histologic feature in early-stage lung adenocarcinoma (LUAD) incorporated into the ninth edition TNM staging. Despite its clinical significance, the molecular features underlying STAS in stage 1 LUAD remain incompletely characterised. Patients with stage 1 LUAD and known STAS status were identified. Whole exome and RNA sequencing were performed on tumour samples with matched normal controls. Disease-free survival (DFS) was analysed using the Kaplan-Meier method and Cox regression. Among 378 patients, 54.2% had STAS+ tumours, with similar incidence between EGFR-mutant and EGFR-wildtype LUAD. STAS+ tumours were significantly associated with stage 1B disease, lymphovascular invasion, higher histological grade, micropapillary or solid predominant adenocarcinoma subtype and PD-L1 tumour proportion score ≥1%. STAS+ remained independently associated with inferior DFS after multivariable adjustment (hazard ratio 2.32, 95% CI 1.16-4.63; p = 0.017). At the molecular level, STAS+ tumours were enriched for TP53 co-mutations, whole genome doubling, non-TRU transcriptomic subtypes and upregulation of cell cycle-related pathways, with directionally consistent findings across EGFR-mutant and EGFR-wildtype tumours. STAS+ in stage 1 LUAD is associated with a distinct molecular phenotype characterised by genomic instability and cell cycle dysregulation, consistent with a more aggressive biological phenotype with implications for risk stratification and adjuvant therapy selection.