Genetic alterations in TRAF3 and CYLD that regulate nuclear factor κB and interferon signaling define head and neck cancer subsets harboring human papillomavirus.

INTRODUCTION In virally induced cancers, nuclear factor jB (NF-jB) transcription factors that promote neoplastic transformation are aberrantly activated, and antiviral innate and adaptive immune responses often are deregulated. However, to our knowledge, the nature and role of the genetic changes required for sustained infection and transformation and their clinical consequences are less clear. Studies from The Cancer Genome Atlas (TCGA) and other sequencing projects recently provided important clues underlying the development and pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs) harboring human papillomavirus (HPV) infection. Deletions or mutations were uncovered in the tumor necrosis factor receptor-associated factor 3 (TRAF3) and cylindromatosis lysine 63 deubiquitinase (CYLD) genes, which previously were implicated in the regulation of NF-jB and antiviral interferon (IFN) signaling in response to other DNA viruses. In this issue of Cancer, Hajek et al provide evidence that deletions or mutations in TRAF3 and CYLD define distinct subsets of HPV-positive (HPV1) HNSCC with associated activation of transcription factor NF-jB, episomal HPV infection of tumors, and improved patient survival.