Zevallos et al. found that HPV(+) HNSCC tumors deriving from heavy smokers (>10 pack-years) have exclusive mutational events of TP53, CDKN2A, KRAS and NOTCH1, and have worse survival than those HPV-positive patients with <10 year-pack year of smoking history. Here, TP53 is linked to head and neck squamous cell carcinoma.