Prospective cohort study of salivary cytokines as biomarkers for predicting oral cancer risk in oral potentially malignant disorders

Oral potentially malignant disorders (OPMDs) are precursor lesions with variable risk of progressing to oral squamous cell carcinoma (OSCC). Reliable biomarkers to predict malignant transformation (MT) are urgently needed. The prospective TWOPMD cohort study at 8 Taiwan healthcare centers evaluated salivary cytokines as biomarkers for predicting MT in OPMD. The authors analyzed 1313 saliva samples from 356 healthy controls, 860 OPMD patients, and 97 OSCC patients. Eight inflammation-related cytokines were quantified using Bio-Plex immunoassay. Cox regression models evaluated 749 OPMD cases with longitudinal follow-up to identify cytokine predictors of MT. Interferon (IFN) signalling was significantly enriched in progressive OPMDs, with IFN signatures correlating strongly with inflammation-related cytokine expression. IL-1β, IL-6, IL-8, TNF-α, and IL-10 were significantly dysregulated across the OPMD, OSCC, and control groups. Cox regression identified IL-6, IL-6/IL-1Ra ratio, and composite index (IL-8 x IL8/IL-1Ra) as significant MT predictors. Kaplan-Meier analyses confirmed that elevated cytokine biomarkers were associated with significantly elevated cancer risk (p=0.02, p=0.00001, p=0.002). The authors conclude that salivary cytokines, particularly IL-6/IL-1Ra ratio, are promising noninvasive biomarkers for predicting oral cancer risk in OPMD (visual abstract).