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

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 (<i>n</i> = 24) using a TCGA-LUAD cohort (<i>n</i> = 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 (Group^Low, Group^Moderate, and Group^High), each exhibiting distinct transcriptomic patterns. Notably, the Group^High showed significantly poor overall survival [OS; hazard ratio (HR) = 1.43, <i>p</i>-value < 10^-3] and disease-free survival (DFS; HR = 1.27, <i>p</i>-value < 10^-3). Univariate and multivariate analysis confirmed that its expression status was an independent prognostic predictor (<i>p</i>-value < 10^-3, HR = 2.18, 95% C.I = 1.26-3.76) of the clinical outcomes, outperforming pathologic grade (<i>p</i>-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 Group^Low, which was associated with a favorable prognosis. By integrating multiple independent cohorts (<i>n</i> = 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 Group^High exhibited frequent mutations in key genes such as <i>KEAP1</i>, <i>LYST</i>, <i>SETD2</i>, and <i>TP53</i>, 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.