Indirect/surrogate HPV indicators, including p16INK4a staining, viral DNA detection by PCR or in situ hybridization (ISH), and the identification of E6/E7 mRNA by RT-PCR or RT-qPCR, can all be used to distinguish between HPV-driven and non-HPV-driven HNSCC. Here, CDKN2A is linked to head and neck squamous cell carcinoma.