Subtype-Specific Prognostic and Molecular Significance of ADGRD1 in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

Background: Adhesion G protein-coupled receptor D1 (ADGRD1), formerly known as GPR133, has been implicated in tumor-associated signaling; however, its histology-specific clinicopathologic and prognostic significance in non-small cell lung cancer (NSCLC) remains incompletely characterized. Methods: Clinical and survival data from The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) cohorts were integrated with harmonized gene-expression data obtained from the Genomic Data Commons (GDC). ADGRD1 expression was dichotomized using a cohort-specific median cutoff and additionally analyzed as a continuous standardized variable. Clinicopathologic associations, Pearson correlations with prespecified subtype-associated genes, Kaplan–Meier survival analyses, and univariate and multivariable Cox proportional hazards regression analyses were performed. Benjamini–Hochberg false-discovery-rate correction was applied to molecular correlation analyses. Independent validation was performed using GSE30219 and GSE50081, followed by random-effects meta-analysis and proportional hazards sensitivity analyses. Results: High ADGRD1 expression was associated with favorable overall survival (OS) in LUAD in both univariate (HR = 0.542, 95% CI = 0.400–0.734, p < 0.001) and clinically adjusted Cox analyses (HR = 0.543, 95% CI = 0.398–0.740, p < 0.001). Continuous-expression analyses showed concordant results, and the association remained significant in an additional LUAD model incorporating EGFR mutation status (HR = 0.611, 95% CI = 0.391–0.956, p = 0.031). High ADGRD1 expression was also associated with favorable recurrence-free survival (RFS) in LUAD. In contrast, high ADGRD1 expression was associated with adverse OS in LUSC in both univariate (HR = 1.444, 95% CI = 1.099–1.898, p = 0.008) and clinically adjusted analyses (HR = 1.501, 95% CI = 1.137–1.982, p = 0.004), whereas RFS was not significantly different. After false-discovery-rate correction, ADGRD1 correlated positively with TP53 expression in LUAD and inversely with CDKN2A, SOX2, and PIK3CA in LUSC. Independent GEO validation supported the favorable LUAD association (pooled HR = 0.675, 95% CI = 0.538–0.847, p < 0.001), whereas the adverse LUSC association was not independently reproduced (pooled HR = 0.909, 95% CI = 0.686–1.204, p = 0.504). Conclusions: ADGRD1 shows histology-dependent prognostic associations in NSCLC. Its favorable association with survival in LUAD was robust across dichotomized and continuous analyses, multivariable adjustment, EGFR-mutation sensitivity analysis, and independent GEO cohorts. In contrast, the adverse association observed in TCGA-LUSC was not reproduced externally. These findings support further evaluation of ADGRD1 as a subtype-specific prognostic marker, particularly in LUAD.