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    Integrated genome-wide DNA methylation and transcriptomic analysis prioritizes EPHA5 as a candidate non-invasive epigenetic biomarker for oral squamous cell carcinoma
    (Frontiers Media S. A., 2026) Demokan, Semra; Özemek, Begüm; Turna, Seval; Cömert, Sevde; Şen, Cömert; Avcı, Kağan; Özkan, Ahmet; Şen, Sena; Poda, Mehveş; Ulusan, Murat; Sezerman, Uğur; Ak, Gülsüm; Alatlı, Fatma Canan; Dalay, Nejat
    Purpose: Oral squamous cell carcinoma (OSCC) remains a major clinical challenge because of delayed diagnosis and the lack of validated non-invasive biomarkers for OSCC detection. Epigenetic alterations during oral carcinogenesis represent promising biomarker candidates. This study aimed to prioritize clinically relevant epigenetic biomarkers and validate EPHA5 using an integrated genome-wide DNA methylation and transcriptomic approach. Experimental Design: Genome-wide DNA methylation and transcriptomic profiling were performed to identify epigenetically deregulated genes in OSCC. Candidate genes were prioritized by integrating DNA methylation, transcriptomic data and biological relevance. EPHA5 was subsequently selected for validation and evaluated by quantitative methylation-specific PCR (QMSP) and quantitative real-time PCR (QRT-PCR) in tissue, saliva and serum samples from independent cohorts comprising patients with OSCC, oral premalignant lesions (OPML) and healthy controls. Results: Genome-wide analysis identified 661 upregulated and 577 downregulated genes together with 2,431 differentially methylated regions corresponding to 1,776 genes. Integrated analysis generated a panel of 51 candidate genes, from which EPHA5 was prioritized using integrated DNA methylation, gene expression, pathway enrichment and biological relevance. EPHA5 promoter hypermethylation was detected in 66.7% of OSCC tumors, whereas concurrent promoter hypermethylation and reduced expression were observed in 28.6% of tumors. Methylation was also detected in 54.5% of OPML lesions and in the saliva of 47.6% of OSCC patients but was rarely detected in healthy controls. Tumor EPHA5 methylation significantly discriminated OSCC from healthy controls (AUC = 0.780, p = 0.004; sensitivity, 71.4%; specificity, 75%). Salivary EPHA5 methylation also significantly discriminated OSCC from healthy controls (AUC = 0.717, p = 0.025; sensitivity, 52.4%; specificity, 87.5%), whereas serum methylation showed no significant diagnostic utility (AUC = 0.571, p = 0.462). Discrimination between OSCC and OPML was limited and did not reach statistical significance (tumor AUC = 0.662, p = 0.068; salivary AUC = 0.600, p = 0.264). Conclusions: Frequent tumor hypermethylation together with detectable salivary methylation supports further evaluation of EPHA5 as a candidate non-invasive epigenetic biomarker for OSCC. However, its moderate diagnostic performance, limited discrimination between OSCC and OPML, and lack of external validation indicate that larger prospective studies and evaluation within multimarker methylation panels are required before clinical implementation.