Comprehensive analysis of genetic and epigenetic factors in oropharyngeal carcinoma: Integrating GWAS data with functional pathway analysis

Abstract

Aim: Oropharyngeal carcinoma (OPC) is a complex malignancy shaped by inherited susceptibility, environmental exposures, and regulatory mechanisms. Despite genome-wide association studies (GWAS) identifying multiple associated loci, their downstream biological relevance and interactions with metabolic and epigenetic factors remain inadequately characterised. This study systematically integrated GWAS-identified genes with functional bioinformatic analyses to elucidate molecular processes contributing to OPC. Methodology: GWAS-implicated genes were subjected to pathway and process enrichment, transcription factor binding prediction, microRNA target enrichment, and cell-type–specific marker identification. Statistical evaluation employed p-values, adjusted p-values, odds ratios, and combined enrichment scores. Associated metabolites and histone modification signatures were examined to contextualise findings within broader regulatory frameworks. Results: Enrichment analyses revealed strong overrepresentation of alcohol-related metabolic pathways, particularly ethanol oxidation (OR = 3331.00), and retinol/retinoic acid metabolism (OR = 1498.13). Significantly associated metabolites included ethanol, acetaldehyde, retinol, and retinal. MicroRNA enrichment implicated miR-3924 and miR-511-3p (OR > 50), whilst epigenetic profiling highlighted H3K27me3 and selected acetylation marks. Cell marker analysis indicated enrichment for LGR5-positive stem cells and basal epithelial cells. Interpretation: These findings outline a multifactorial landscape in oropharyngeal carcinoma, wherein genetic susceptibility modulated through epigenetic and cell-type–specific regulatory contexts, offering candidate features for future experimental validation. Key words: Alcohol metabolism, Epigenetic regulation, Genome-wide association study, Oropharyngeal carcinoma, Retinol metabolism