A Targeted Bioinformatics Assessment of Adrenocortical Carcinoma Reveals Prognostic Implications of GABA System Gene Expression.

Erika L Knott,Nancy J Leidenheimer

doi:10.3390/ijms21228485

Erika L Knott, Nancy J Leidenheimer

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https://doi.org/10.3390/ijms21228485

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Adrenocortical carcinoma (ACC) is a rare but deadly cancer for which few treatments exist. Here, we have undertaken a targeted bioinformatics study of The Cancer Genome Atlas (TCGA) ACC dataset focusing on the 30 genes encoding the γ-aminobutyric acid (GABA) system—an under-studied, evolutionarily-conserved system that is an emerging potential player in cancer progression. Our analysis identified a subset of ACC patients whose tumors expressed a distinct GABA system transcriptome. Transcript levels of ABAT (encoding a key GABA shunt enzyme), were upregulated in over 40% of tumors, and this correlated with several favorable clinical outcomes including patient survival; while enrichment and ontology analysis implicated two cancer-related biological pathways involved in metastasis and immune response. The phenotype associated with ABAT upregulation revealed a potential metabolic heterogeneity among ACC tumors associated with enhanced mitochondrial metabolism. Furthermore, many GABAA receptor subunit-encoding transcripts were expressed, including two (GABRB2 and GABRD) prognostic for patient survival. Transcripts encoding GABAB receptor subunits and GABA transporters were also ubiquitously expressed. The GABA system transcriptome of ACC tumors is largely mirrored in the ACC NCI-H295R cell line, suggesting that this cell line may be appropriate for future functional studies investigating the role of the GABA system in ACC cell growth phenotypes and metabolism.

Highlights

Adrenocortical carcinoma (ACC) is a rare type of adrenal malignancy diagnosed in approximately 1 out of every 1 million people in the United States
For each of the 30 genes encoding the γ-aminobutyric acid (GABA) system genes (Table 1), ACC tumors were examined for mutations, copy number alterations (CNA), RNA-seq expression levels, and methylation status
Through gene ontology analysis of 455 overexpressed genes and 264 underexpressed genes, we identified two biological pathways enriched in tumors with upregulated ABAT: “mesenchymal to epithelial transition” (MET) and “interferon gamma signaling” (Table 5)—both of which are related to decreased cancer progression [22,23]

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Adrenocortical carcinoma (ACC) is a rare type of adrenal malignancy diagnosed in approximately 1 out of every 1 million people in the United States. Surgery is the primary treatment for ACC. ACC originates from neuroendocrine foci in the adrenal cortex [4]. Investigations into developing novel ACC treatments have largely targeted steroidogenic pathways. Inhibition of steroidogenesis enzymes with clinically available drugs such as ketoconazole, metyrapone, and aminoglutethimide does not affect the progression of the ACC tumors; these drugs are recommended only as adjuvant treatment and/or for symptom management [6]. Radiotherapy targeting steroidogenesis enzymes results in moderate success in a very small ACC patient cohort [11]. While treatment with the adrenolytic agent mitotane results in ACC tumor regression in roughly half of patients across multiple studies, this drug is severely toxic [6]

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