Epigenetic Regulation of Oral Submucous Fibrosis Progression and Malignant Transformation in a Cohort from South West Nigeria

Oral submucous fibrosis (OSMF) is a chronic, potentially malignant mucosal condition characterized by progressive submucosal fibrosis and restricted mouth opening. Although areca nut chewing is its primary etiological driver globally, OSMF in Nigerian populations is associated with additional local habits including tobacco chewing and consumption of certain spiced preparations. Its rate of malignant transformation and the epigenetic mechanisms governing this transition remain incompletely characterized in West African populations. This original PhD study investigates the role of epigenetic alterations, specifically promoter hypermethylation of tumor suppressor genes (p16, CDH1, and DAPK) and global DNA methylation patterns, in the progression of OSMF and malignant transformation to oral squamous cell carcinoma in a cohort of 80 OSMF patients and 30 OSMF-derived OSCC cases attending maxillofacial surgery clinics at UCH Ibadan, OAUTHC Ile-Ife, and LUTH Lagos, South West Nigeria. Tissue specimens were analyzed by methylation-specific PCR and pyrosequencing. Functional fiber band staging and immunohistochemical profiling for Ki-67 and p53 complemented the molecular analysis. Results demonstrate significantly higher frequency of p16 and DAPK promoter hypermethylation in OSMF-derived OSCC compared to uncomplicated OSMF, suggesting a methylation-mediated silencing of key cell cycle regulatory genes during malignant transformation. Global DNA hypomethylation correlated with advanced fibrosis staging. The study contributes original epigenetic data to the OSMF malignant transformation pathway in a Nigerian population and proposes epigenetic biomarkers as predictive tools for surveillance. Keywords: oral submucous fibrosis, epigenetics, DNA methylation, malignant transformation, South West Nigeria.