Oral potentially malignant disorders (OPMDs), such as oral lichen planus (OLP) and oral leukoplakia (OLK), are clinical conditions associated with the risk of developing oral squamous cell carcinoma
however, no standardized treatment guidelines exist. Mutations in specific genes, known as oral cancer driver gene mutations (ODGMs), are responsible for carcinogenesis. We aimed to analyze the ODGMs in OPMDs and investigate their clinical correlations. We investigated 41 cases of OPMDs, including OLP and OLK, and performed next-generation sequencing using a custom gene panel targeting whole exons of TP53, HRAS, PIK3CA, NOTCH1, CDKN2A, FBXW7, and BRAF. We detected ODGMs in four OLK cases and one OLP case. All ODGM-positive OLK cases were located in the tongue, a site associated with a higher risk of malignant transformation compared with those in other oral sites. Moreover, ODGMs were significantly associated with alcohol consumption. While there was a tendency for mutations to increase with higher grades, we found no significant correlation between the presence of ODGMs and oral epithelial dysplasia (OED) grade. Notably, in the case of OLP with ODGM, the lesion histopathologically developed OED during the follow-up period, indicating an increased risk of cancer development and that cases with identified ODGMs require early surgical excision. These findings suggest that ODGM analysis may predict the risk of cancer development in OPMDs that are difficult to diagnose using histopathological examination alone.