Intriguingly, recent genomic studies of HNSCC by The Cancer Genome Atlas (TCGA) as well as other groups identified deletions or mutations in TNF-receptor associated factor (TRAF3) and Cylindromatosis (CYLD; Turban Tumor Syndrome) that were previously implicated in NF-κB and anti-viral Interferon responses. Hajek et al find genomic alterations in TRAF3/CYLD define distinct subsets of HPV+ HNSCC with associated activation of transcription factor NF-κB, episomal HPV infection of tumors, and improved survival of patients.