Novel Disease-Specific Panel of Salivary microRNAs for the Detection of Oral Squamous Cell Carcinoma from Early Invasion to Stage IV Disease

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Abstract
Oral squamous cell carcinoma (OSCC) is characterized by consistently high mortality rates (≤60%) despite therapeutic advances. This is attributable to diagnostic delays arising from the asymptomatic early stages and time-consuming protocols. Hence, the establishment of reliable biomarkers for the routine assessment of the oral mucosa is imperative. MicroRNAs (miRNAs), key epigenetic regulators of gene expression, represent ideal candidates given their characteristic dysregulation across different pathologies. Here, we aimed to identify novel OSCC-specific miRNAs for the saliva-based detection of OSCC from the presymptomatic stage of early invasion. Through a multistep bioinformatic workflow, four miRNAs (miR-20b-5p, miR-484, miR-185-5p and miR-181d-5p) were identified as disease-specific since they simultaneously regulated >65% of a panel encompassing the 15 primarily overexpressed oncogenes in OSCC and a stage-specific panel including the six upregulated genes that genetically define the malignant stages of sequential oral carcinogenesis. The salivary expression of the identified miRNAs was studied in 31 OSCC patients and 31 healthy controls, using quantitative real-time PCR, followed by statistical analysis and an evaluation of the diagnostic accuracy. All studied miRNAs were significantly downregulated in the saliva of OSCC patients compared to controls (miR-484, p < 0.001; miR-181d-5p, p < 0.001; miR-185, p = 0.008; miR-20b, p = 0.026) and exhibited combinatory diagnostic performance of 95.4% (p < 0.001) for OSCC detection. Their expression remained uninfluenced by lifestyle and clinicopathological parameters, including smoking/alcohol, tumor site, grade and disease stage. The proposed 4-miRNA panel exhibits high diagnostic performance for the early, saliva-based detection of OSCC, irrespective of histopathological and lifestyle confounders, highlighting its potential as a robust non-invasive screening tool.

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