We identify multiple key molecular features of HPV-driven HNSCC and CESC, including the absence of TP53 mutations in p16 positive HPV-associated SNSCC, the presence of hotspot mutations in PIK3CA and FGFR3, APOBEC-associated mutational signature enrichment, HPV viral integration at known hotspot locations, and frequent mutations in epigenetic regulators6,16,21,24. This evidence concerns the gene TP53 and head and neck squamous cell carcinoma.