On the basis of mutational features, such as the absence of mutational hotspots and the presence of nonsense mutations, it is hypothesized that NOTCH1 acts as a tumor suppressor in HNSCC.182 Notch signaling has been demonstrated as a tumor suppressor in epithelial SCC malignancies (lung, bladder, and esophageal tumors) and several in vivo models.159. This evidence concerns the gene NOTCH1 and head and neck squamous cell carcinoma.