Considering that NF-κB is activated in various tumor types, and its activity promotes carcinogenesis through cellular proliferation, transformation, and angiogenesis, while protecting tumor cells from apoptosis (55), we hypothesize that activation of NF-κB due to genetic alterations in NF-κB regulators (e.g., TRAF3 or CYLD, Fig. 4) in the context of permissive epigenetic landscape promoting expression of NF-κB target genes (Fig. 6H) represents a distinct pathway for HPV16 mediated oncogenesis in the oropharynx (SI Appendix, Fig. S6). Here, CYLD is linked to neoplasm.