Integrated Analysis Identifies CCNA2 as a Candidate Diagnostic and Prognostic Biomarker in Oral Tongue Squamous Cell Carcinoma

Abstract

Background: Oral tongue squamous cell carcinoma (OTSCC) is an aggressive malignancy with poor prognosis, necessitating reliable biomarkers. Methodology: Genes with significantly higher expression in OTSCC tumor tissues compared to normal tongue tissues were identified via integrated transcriptomic analysis of seven GEO datasets. To assess their diagnostic and prognostic potential, these genes were further characterized using multi-omic and clinical data from the TCGA-OTSCC and CPTAC-OTSCC cohorts. Results: A total of 1,117 genes were found to be upregulated in OTSCC tissues, among which only CCNA2 (Cyclin A2) was significantly associated with both reduced overall survival (OS) and disease-free survival (DFS) in the TCGA-OTSCC cohort (n=128), based on Cox proportional hazards regression and Kaplan-Meier analyses. CCNA2 showed moderate prognostic performance (AUC=0.63 for OS; AUC=0.65 for DFS) and was significantly upregulated in higher-grade tumors (p=0.01) and in deceased patients (p=0.03). No somatic mutations or promoter methylation alterations were observed in CCNA2 based on TCGA data. In CPTAC-OTSCC samples (n=18), CCNA2 protein expression was significantly higher in tumor tissues than in non-tumoral tissues (p <0.0001), with a positive correlation between mRNA and protein levels (r=0.56, p=0.01). Both mRNA and protein forms showed strong diagnostic performance (AUC=0.92 and AUC=0.82, respectively), consistent with observations across multiple tumor types. While CCNA2 protein levels showed prognostic relevance for OS (AUC=0.69, p=0.01), the mRNA-based prediction did not reach statistical significance (AUC=0.63, p=0.36). Functional enrichment analysis of CCNA2 co-expressed genes predicted involvement in cell cycle, mismatch repair, and DNA replication pathways. Additionally, protein-protein interaction analysis positioned CCNA2 as a central hub, suggesting its potential role in OTSCC pathogenesis. Conclusions: These findings indicate that CCNA2 is a promising diagnostic and prognostic biomarker candidate in OTSCC. Given the small size of the CPTAC validation cohort, further studies in larger, independent OTSCC cohorts are warranted to confirm its clinical utility.