SMAD4 is the most common SMAD family protein disrupted in cancers, and its functional loss or repression has been reported at high frequencies in pancreatic cancer, head and neck squamous cell carcinoma (HNSCC), and CRC, as well as in biliary, bladder, breast, liver, lung, and esophageal cancers [24]. The gene discussed is SMAD4; the disease is head and neck squamous cell carcinoma.