Clinical and Molecular Associations of ITGB1 Expression in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma: A TCGA-Based Study

Background/Objectives: Integrin beta 1 (ITGB1) participates in cell–extracellular matrix signaling, but its associations with clinical outcomes and molecular features in non-small cell lung cancer (NSCLC) may vary by histological subtype. We reassessed its clinical and transcriptomic associations in TCGA lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), explicitly testing interaction effects and microenvironmental confounding. Methods: Primary-tumor RNA-sequencing profiles from 492 LUAD and 488 LUSC patients were linked to standardized TCGA Clinical Data Resource outcomes. We performed median-based Kaplan–Meier analysis; Cox models of continuous ITGB1 expression per within-subtype standard deviation, with stage-stratified clinical adjustment; a common nine-gene expression correlation panel; ESTIMATE-score sensitivity analyses; tumor DNA mutation/copy-number comparisons; and phenotype-permutation Hallmark gene set enrichment analysis (GSEA). Results: After clinical and stromal/immune score adjustment, elevated ITGB1 expression was significantly associated with poor overall survival in LUAD (hazard ratio [HR] = 1.357, 95% confidence interval [CI]: 1.145–1.610) and favorable overall survival in LUSC (HR = 0.741, 95% CI: 0.627–0.876). Higher ITGB1 expression was also associated with PFI in LUAD (HR 1.240) and LUSC (HR 1.333), but survival interaction by histology was not significant (OS p = 0.198; PFI p = 0.724). ITGB1 correlations with KRAS and PIK3CA were stronger in LUAD than LUSC even after microenvironmental adjustment. SOX2 and PIK3CA amplification showed significant histology interactions with ITGB1 expression (adjusted interaction β = −0.651 and −0.613). Gene set enrichment analysis (GSEA) revealed within-cohort enrichment patterns associated with ITGB1 expression, highlighting pathways such as EMT, angiogenesis, and coagulation in LUAD, whereas MYC Targets, E2F Targets, and DNA Repair were enriched in LUSC. These findings represent within-cohort enrichment patterns and do not establish statistically significant differences between histologies. Conclusions: ITGB1 exhibits histology-associated molecular and microenvironmental patterns, without convincing evidence of differing survival hazard ratios between LUAD and LUSC. These retrospective findings require independent and functional validation.