While Notch gain-of-function mutations have been demonstrated in T-cell leukemias and some other forms of cancer, a tumor suppressor role for the Notch pathway has also been suggested in a number of human cancers, including in HNSCC, in which NOTCH1 LOF mutations were found in 10–15 % of tumors and abnormalities of the Notch pathway in 66 % of patients [18]. The gene discussed is NOTCH1; the disease is cancer.