Expression Profile and Clinical Relevance of ADAR Family Genes in Head and Neck Squamous Cell Carcinoma

<b>Background:</b> ADAR1 (<i>ADAR</i>), ADAR2 (<i>ADARB1</i>), and ADAR3 (<i>ADARB2</i>) are deaminase adenosine RNA-specific enzymes that play a significant role in RNA metabolism. ADAR1 (<i>ADAR</i>) and ADAR2 (<i>ADARB1</i>) catalyze A-to-I editing and ADAR3 (<i>ADARB2</i>) plays a regulatory role. The role of these three genes still remains unknown in head and neck cancers (HNSCC). The aim of this study is to reveal the role of deaminase adenosine RNA-specific enzymes in pathomechanisms of HNSCC and to investigate their potential utility as diagnostic and/or prognostic biomarkers. <b>Methods:</b> The quantitative PCR analysis was conducted using RNA isolated from 22 pairs of matched tumor and adjacent normal tissues, 76 formalin-fixed paraffin-embedded (FFPE) tumor samples, and a panel of HNSCC cell lines (DOK, SCC-25, SCC-40, FaDu, and CAL-27). In parallel, transcriptomic and clinical data from the Cancer Genome Atlas HNSCC cohort were analyzed. Patients were stratified into high- and low-expression groups, and statistical assessments included overall survival and progression-free interval analyses, evaluation of gene expression in relation to clinicopathological parameters, correlation with other genes, and functional pathway exploration using gene set enrichment analysis. <b>Results:</b> ADARB2 was significantly downregulated in HNSCC tumor tissues compared to adjacent normal mucosa (<i>p</i> = 0.044), with discriminatory potential to distinguish malignant from non-malignant tissues (AUC = 0.692, <i>p</i> = 0.029). TCGA data confirmed <i>ADAR</i> (<i>p</i> < 0.0001) and <i>ADARB1</i> (<i>p</i> < 0.0001) upregulation in tumors, while <i>ADARB2</i> was markedly reduced (<i>p</i> = 0.04). Patients with high <i>ADARB2</i> expression showed significantly longer overall survival (pa = 0.0121; pb = 0.0098), with a trend toward improved progression-free survival (pb = 0.0681). Subsite analysis revealed high <i>ADAR</i> expression correlated with poor OS in pharyngeal tumors (<i>p</i> < 0.05), whereas high <i>ADARB2</i> expression was linked to improved DFS (pa = 0.0023, pb = 0.0047). GSEA indicated that low <i>ADARB2</i> expression was enriched in oncogenic pathways, including Wnt/β-catenin (<i>p</i> = 0.006), MYC targets (<i>p</i> = 0.009), and TGF-β1 (<i>p</i> = 0.009). <b>Conclusions:</b><i>ADARB2</i> expression was significantly reduced in HNSCC tumor tissues compared to normal mucosa and demonstrated strong discriminatory power for distinguishing malignant from non-malignant samples. High <i>ADARB2</i> expression was associated with markedly improved overall survival, whereas low expression correlated with enrichment of oncogenic pathways, including Wnt/β-catenin, Notch, and Hedgehog, consistent with a poorer clinical prognosis. These findings highlight <i>ADARB2</i> as a promising diagnostic biomarker and independent prognostic factor in HNSCC.