Integrative pan-cancer analysis of GAD1 across molecular subtypes, metabolic contexts, and clinical outcomes

Glutamate decarboxylase 1 (GAD1) catalyzes the conversion of glutamate to gamma-aminobutyric acid (GABA) and has been implicated in individual malignancies, but its cross-cancer heterogeneity and clinical independence remain incompletely defined. We integrated TCGA and GTEx expression data, established TCGA molecular subtypes, Cancer Cell Line Encyclopedia (CCLE) transcriptomic and metabolomic data, epigenomic and genomic features, immune correlates, clinical outcomes, drug-response resources, and single-cell and spatial transcriptomic datasets. Parallel pan-cancer tests were controlled using the Benjamini-Hochberg false-discovery rate (FDR). GAD1 was dysregulated in multiple cancers and differed among established molecular subtypes in 11 of 17 evaluable TCGA cancer types. Among 913 CCLE cell lines with matched expression and metabolite profiles, lineage-adjusted analysis identified an inverse association between GAD1 and C18:1 lysophosphatidylcholine (rho = -0.130, FDR = 0.019); the association with GABA was positive but did not meet the FDR threshold (rho = 0.113, FDR = 0.068). Multivariable Cox models treated GAD1 as a continuous cancer-specific z score and adjusted for age, stage, and molecular subtype when supported by data completeness and event counts. Higher GAD1 remained associated with shorter overall survival in liver hepatocellular carcinoma and mesothelioma after endpoint-specific FDR correction, whereas most univariate signals attenuated. The remaining multi-omic, immune, drug-response, single-cell, and spatial results provide convergent but observational context. These findings position GAD1 as a context-dependent candidate for mechanistic and externally validated clinical studies rather than an established pan-cancer biomarker or therapeutic target.