In HPV- HNSCC is driven by deletions in cell cycle regulatory genes (CDKN2A, CCBD1, TP53), mutations in WNT signaling genes (FAT1, AJUBA, NOTCH1), mutations in epigenetic regulation genes (KMT2D, NSD1), and amplification of cell growth genes (EGFR), many of which are also implicated in other malignancies linked to tobacco use [21–23]. Here, TP53 is linked to head and neck squamous cell carcinoma.