Identification of a three-gene prognostic signature associated with tumor immune characteristics in lung adenocarcinoma: A comprehensive analysis of multi-omics data

Abstract

Lung adenocarcinoma (LUAD) is a highly heterogeneous malignancy with substantial differences in clinical outcomes and therapeutic responses. However, robust molecular signatures integrating prognostic stratification with tumor biological and immune characteristics remain limited. In this study, we established and validated a three-gene prognostic signature consisting of KRAS, KIAA1109, and BRCA1 through stepwise multivariate Cox regression analysis. The signature demonstrated robust prognostic performance across multiple independent cohorts. High-risk patients exhibited enrichment of cell cycle- and DNA repair-associated pathways, accompanied by distinct tumor microenvironment landscapes and altered immune infiltration patterns. Further analyses revealed that the high-risk group displayed lower TIDE scores, higher tumor mutation burden, and distinct immunotherapy-associated characteristics in the IMvigor210 cohort, suggesting potential differences in responsiveness to immune checkpoint blockade. Among the three signature genes, BRCA1 was selected for functional validation. Consistent with the bioinformatic analyses, BRCA1 was markedly upregulated in LUAD tissues and cultured LUAD cells, and its depletion suppressed malignant phenotypes in vitro. Collectively, our findings establish a clinically relevant prognostic signature integrating survival prediction, tumor microenvironment characteristics, and immune-related biological features in LUAD. This study provides a biologically interpretable framework for prognostic stratification and characterization of tumor heterogeneity in LUAD.