Transcriptomic Profiling Reveals METTL26 as a Potential Biomarker in Head and Neck Squamous Cell Carcinoma with Independent Validation in Oral Squamous Cell Carcinoma

Background: Methyltransferase-like 26 (METTL26) is a poorly characterized member of the METTL family that has been included in previous pan-cancer analyses, but its disease-specific clinical and molecular relevance in head and neck squamous cell carcinoma (HNSCC) and oral squamous cell carcinoma (OSCC) remains poorly defined. The aim of this study was to investigate METTL26 expression and its potential clinical and biological relevance in HNSCC, with particular attention to OSCC. Methods: The TCGA-HNSC dataset was used as a discovery dataset. METTL26 expression and pathological stage were evaluated using GEPIA3, whereas survival associations were analyzed in R. Tumor microenvironment associations were investigated using TIMER3. Genes co-expressed with METTL26 were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, while protein interaction networks were explored using STRING. These discovery analyses were performed using the heterogeneous TCGA-HNSC cohort, whereas two independent OSCC cohorts (GSE37991 and GSE30784) were primarily used to validate differential expression. Results: METTL26 expression was significantly increased in TCGA-HNSC compared to normal tissues and was associated with pathological stage. High METTL26 expression showed a non-significant trend toward poorer OS and PFI and was not independently associated with either outcome after multivariable adjustment. A positive association with cancer-associated fibroblast (CAF) abundance was detected using TIDE, whereas an inverse association with endothelial cell abundance was observed across multiple algorithms. Functional analysis showed enrichment of mitochondrial gene expression, mitochondrial translation, ribosomal functions, oxidative phosphorylation, and reactive oxygen species-related pathways. METTL26 was also positively correlated with several genes involved in therapy response such as PTOV1, MIF, BAD, and EIF3C. Importantly, METTL26 upregulation was independently confirmed in both OSCC cohorts, GSE37991 and GSE30784. Conclusions: METTL26 upregulation was independently confirmed in two OSCC cohorts, supporting its potential relevance as an expression biomarker. In contrast, the observed associations with pathological stage, mitochondrial and redox-related programs, stromal composition, and therapy-response-related genes should be considered exploratory and hypothesis-generating and require independent and functional validation.