Genomic signature driving preinvasive to invasive processes in stage I lung adenocarcinoma

Progression from minimally invasive adenocarcinoma (MIA) to invasive adenocarcinoma (IA) in lung adenocarcinoma (LUAD) is associated with a significantly worse prognosis and lacks predictive markers. The genomic molecular mechanisms of progression and genetic signatures mediating the MIA to IA transition in early-stage LUAD are still largely uncharacterized. In our study, a genomic signature driving MIA to IA was developed by 243 MIA and 532 IA stage I LUAD patients, and its ability to predict outcomes was validated in multiple cohorts. Among patients with stage I LUAD, 19 genes exhibited significant differences in frequency between MIA and IA groups, with notable enrichment in the MAPK, PI3K-Akt and ErbB pathways. A genomic signature of 11 genes associated with LUAD invasion progression, with TP53 and CDKN2A playing key functional roles, was developed and correlated with poor prognosis by internal and external cohorts (p < 0.05). The high-risk group exhibited elevated tumor mutational burden, mutation-allele tumor heterogeneity, and variant allele frequency values both in train and validation cohorts (p < 0.001). Mixed ground-glass opacity and solid nodules, predominantly larger than 1 cm, were more common in the high-risk population (p < 0.001), while the low-risk group exhibited a higher proportion of high-medium differentiated LUAD (p < 0.001). Our results reveal an 11-gene genomic signature driving invasive progression from MIA to IA associated with poor outcome in stage I LUAD patients by validating internal and external cohorts, radiological, pathological and tumor size, with potential future implications for disease monitoring, prognosis, and future therapeutic interventions.