Abstract 4401: GABA system expression level changes persist across cancers of many organ systems

Abstract

The gamma-aminobutyric acid (GABA) system is evolutionarily conserved and, in mammals, is comprised of 30 genes encoding 4 enzymes, 21 receptor subunits, and 5 transporters. The GABA system has primarily been studied for its role in inhibitory neurotransmission in the brain; however, the physiological importance of this system in peripheral tissues is less well-recognized. Although a few GABA system components have been linked to cancer progression, this information is disparate, limited, and largely unsupervised. Here, we undertook a systematic bioinformatics investigation. To this end, we accessed RNA-seq / microarray transcript data and mass spectrometry / immunohistochemistry protein data from patient tumor datasets within The Cancer Genome Atlas (TCGA), NCBI's Gene Expression Omnibus (GEO), and the NCI's Clinical Proteomic Tumor Analysis Consortium (CPTAC). In order to visualize / analyze data, bioinformatics user-interface platforms were used, including cBioPortal, the Human Protein Atlas, UALCAN, and KM-Plotter. Kaplan-Meier survival curves, differential gene expression between tumor vs. normal samples (across cancer subtypes and stages), and targeted gene set enrichment / correlations were assessed. Several GABA system genes - such as ABAT, GABRP, and GABBR1 - were commonly altered across the >13 cancer types examined (including reproductive, digestive, and secretory and solid organ tumors). Unexpectedly, other transcripts such as ALDH5A1 were highly expressed across all cancers (RNA-seq log2 RSEM median value ~9). Based on Kaplan-Meier survival curve analysis, 11 GABA system genes were identified as prognostic markers for at least one type of cancer (log-rank P value < 0.001 when analyzed using optimized cutoff values; average FKPM > 1). Furthermore, 19 of the 30 investigated genes showed significant alterations in transcript levels between normal adjacent vs. tumor tissues (p < 0.05; minimum median expression = 1 TPM) in at least one cancer type. Interestingly, unique transcript expression patterns of GABA system genes were found among cancer subtypes, such as between triple-negative vs. ER+ breast cancers. Our efforts seek both to identify cancers that leverage the GABA system for their progression, and also to provide a basis for subsequent hypothesis-driven experimentation. Additionally, the data analyzed herein may reveal opportunities to repurpose drugs for cancer treatment, as there are a variety of GABA system-targeting therapeutic agents used to treat neurological and psychiatric disorders. We thank the LSU Health School of Graduate Studies and Feist-Weiller Cancer Center for support. Citation Format: Erika Lynn Knott, Nancy J. Leidenheimer. GABA system expression level changes persist across cancers of many organ systems [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4401.