Bitter taste receptors as prognostic markers in adrenocortical carcinoma.
Authors: Yasin Jehad , Younis Osama , Saeed Ahmad , Alkuttob Leen , Odat Ramez , Hammadeh Bara , Nguyen Dang 
Published: August 2024

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Background: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm of the adrenal gland. Progressive forms of this cancer carry a dismal prognosis with 5-year survival rates < 40%. As such, predictors of stage progression and prognostic biomarkers are a must. Taste 2 receptors (TAS2Rs) are localized on the surface of bitter receptor cells. Recent evidence has shown their role as prognostic biomarkers in multiple cancers, such as breast, prostate, and head and neck squamous cell carcinoma. The aim of this study was to elucidate the role of TAS2Rs in ACC. Methods: Differentially expressed genes (DEGs) based on high and low expression groups of TAS2R genes were identified through the 'DESeq2' package on R. Subsequent Gene Set Enrichment Analysis (GSEA) was performed using the 'TCGAbiolinks' package on R and Enrichr online tool. Immune infiltration analysis was conducted using TIMER2.0 and CIBERSORT. Survival analysis with an optimal expression cutoff for overall survival (OS) and a median cutoff for disease-free survival (DFS) based on The Cancer Genome Atlas Adrenocortical carcinoma (TCGA-ACC) data was executed using the 'survival' and 'survminer' R packages and GEPIA2 online tool. Results: Analysis of the TCGA-ACC cohort revealed OS estimates that indicated worse survival in patients with higher TAS2R14, TAS2R19, TAS2R20, and TAS2R30 expression (Table). Further analysis produced consistent results, demonstrating that elevated expressions of TAS2R14 and TAS2R19 are correlated with decreased DFS, with Hazard Ratios (HR) of 2.60 (p = 0.0046) and 2.20 (p = 0.022), respectively. Furthermore, the F-test and stage plots have shown consistent upregulation of selected TAS2R genes across stages I–IV (p < 0.05). RNA-seq analysis revealed 1170 common (579 downregulated, 591 upregulated) DEGs between high and low TAS2R14 and TAS2R19 expression groups. GSEA showed upregulated genes in high expressers have relations to hedgehog signaling, epithelial to mesenchymal transition, TGF-B signaling, and organization of the extracellular matrix. On the other hand, down-regulated genes showed functions in metabolic reprogramming, chemokine receptor binding, MHC protein complex, and chemokine-mediated inflammation. GSEA on co-expressed genes showed pathways related to ferroptosis, autolysosome activity, and iron homeostasis and metabolism. Immune infiltration analysis revealed significantly increased CD4+, naïve and plasma B cell infiltration with higher TAS2R14 and TAS2R19 expression (Rho > 0.25, p < 0.05), in addition to increased M1 macrophage infiltration with higher TAS2R19 expression (Rho = 0.28, p < 0.05). Conclusions: TAS2R genes are potentially involved in modulating carcinogenic processes, including stage progression, metastasis and invasion, immune regulation, and metabolic processes. This modulation may explain the poorer prognostic outcomes in ACC patients with elevated TAS2R expression. Further validation in external cohorts is necessary to confirm these results. [Table: see text]