The most common genomic abnormalities in HPV(−) HNSCC from smokers are seen in TP53 encoding p53 and CDKN2A encoding p16 with a distinct smoking signature, while the tumors from non-smokers have TP53 mutations with aging and ultraviolet light exposure signatures [32,33,34]. The gene discussed is TP53; the disease is head and neck squamous cell carcinoma.