Unveiling oral cancer's molecular blueprint: A novel classification to guide precision therapy

Oral cancer poses a significant health challenge in Southeast Asia, with a high incidence and mortality. Despite extensive genomic research, a molecular classification for this disease is lacking. This study aimed to address this gap by proposing a molecular classification of oral cancer based on genetic alterations. We conducted a comprehensive literature search on PubMed, identifying 8176 articles related to oral cancer genomics. From these, we selected studies focusing on genomics and compiled a list of 48 genes implicated in carcinogenesis, cross-referencing our findings with the TCGA database. Using cluster analysis and gene ontology, we grouped these genes by function and interactions, and then constructed protein-protein interaction networks to develop our proposed classification. Our results categorize the genes into five main groups: cell-cycle dysregulation (including growth activation and apoptotic dysregulation), immune-mediated, xenobiotic metabolism-associated, inflammatory pathway activation, and viral protein activation. Cell-cycle dysregulation was the most frequently studied, affecting over 60 % of cases, with TP53 being the most common alteration. While immune-mediated and inflammatory pathways are recognized for their therapeutic relevance, xenobiotic and viral mechanisms remain less explored. This review provides the first molecular classification of oral cancer, identifying five key carcinogenic pathways. This framework is expected to improve our understanding of the molecular diversity of oral cancer and guide the development of targeted therapies, especially for understudied pathways like xenobiotic metabolism and inflammation.