Through LASSO regression, 15 DEEGs (AGRN, EXPH5, CLIC4, TSPAN6, TGFBR3, FN1, MMP9, KRT13, THY1, HBA1, FCGBP, PFN2, BST2, EPCAM, and PIP) were identified as critical markers for predicting HNSCC development. Here, TSPAN6 is linked to head and neck squamous cell carcinoma.