Genomic and transcriptomic landscape of spread through air spaces in stage 1 lung adenocarcinoma

Spread throuth air spaces (STAS) is an adverse histologic feature in early-stage lung adenocarcinoma (LUAD). Molecular features underlying STAS in stage 1 LUAD are incompletely characterized. A study at the National Cancer Centre of Singapore, Singapore General Hospital, and the Agency for Science, Technology, and Research in Singapore investigated the genomic and transcriptomic landscape of STAS in stage 1 LUAD. Among 378 patients, 54.2% had STAS+ tumors, with similar incidence between EGFR-mutant and EGFR-wildype LUAD. STAS+ tumors were significantly associated with stage 1B disease, lymphovascular invasion, higher histological grade, micropapillary or solid predominant adenocarcinoma subtype and PD-L1 tumor proportion score ≥ 1. STAS+ was independently associated with inferior disease-free survival, also after multivariable adjustment (HR 2.32; p=0.017). At the molecular level, STAS+ tumors were enriched for TP53 co-mutations, whole-genome doubling, non terminal respiratory unit (TRU) transcriptomic subtypes, and upregulation of cell cycle-related pathways, with directionally consistent findings across EGFR-mutant and EGFR-wildtype tumors. The authors conclude that STAS+ in stage 1 LUAD is associated with a distinct molecular phenotype characterized by genomic instability and cell cycle dysregulation.