Identification of Molecular Subtypes and Prognostic Traits Based on Chromosomal Instability Phenotype-Related Genes in Lung Adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) exhibits significant molecular heterogeneity; however, previous studies have not fully explored its classification into distinct molecular subtypes. Here, we identified LUAD-significant chromosomal instability (CIN) phenotype genes (n = 24) using a TCGA-LUAD cohort (n = 592) and evaluated their ability to predict pathologic grade. Unsupervised clustering and principal component analysis revealed that LUAD patients could be classified into CIN phenotype-related subtypes (GroupLow, GroupModerate, and GroupHigh), each exhibiting distinct transcriptomic patterns. Notably, the GroupHigh showed significantly poor overall survival [OS; hazard ratio (HR) = 1.43, p-value < 10？3] and disease-free survival (DFS; HR = 1.27, p-value < 10？3). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (p-value < 10？3, HR = 2.18, 95% C.I = 1.26？3.76) of the clinical outcomes, outperforming pathologic grade (p-value < 10？3, HR = 1.2, 95% C.I = 1.08？1.33). Moreover, analysis of surfactant metabolism-related genes revealed higher expression in the GroupLow, which was associated with a favorable prognosis. By integrating multiple independent cohorts (n = 779), we validated these findings and confirmed that CIN phenotype gene status serves as a critical prognostic marker in LUAD. Furthermore, genomic profiling showed that the GroupHigh exhibited frequent mutations in key genes such as KEAP1, LYST, SETD2, and TP53, with oncogenes in this group preferentially showing copy number gains. Our study highlights the significance of CIN phenotype gene status as a predictor of LUAD prognosis and its association with transcriptomic and genomic alterations, paving the way for further clinical validation and potential therapeutic interventions.