Although mutation and homozygous deletion of SMAD4 were rare in head and neck squamous cell carcinoma (HNSCC)[17], knockout SMAD4 could lead to spontaneous oral squamous cell carcinoma development in an animal model[18], suggesting the tumor suppressor role of SMAD4 in oral tumorigenesis. The gene discussed is SMAD4; the disease is head and neck squamous cell carcinoma.