HPV Integration in Head and Neck Squamous Cell Carcinomas: Cause and Consequence.

Human papillomaviruses (HPVs) are a necessary cause of anogenital squamous cell carcinomas (SCC) and a subgroup of head and neck SCC, i.e., those originating in the oropharynx. The key events in high-risk HPV (HRHPV)-associated neoplastic progression include persistent infection, deregulated expression of virus early genes in basal epithelial cells, local immune suppression and the accumulation of chromosomal alterations. Evidence for these events particularly comes from studies of uterine cervical carcinogenesis; primary premalignant HRHPV-positive lesions of the head and neck mucosa are seldomly detected. Integration of virus DNA into host chromosomes is considered an important driver of carcinogenesis and observed in 40 up to 90 % of uterine cervical SCC (UCSCC) and oropharyngeal SCC (OPSCC), dependent on the integration detection method used and HRHPV type. In OPSCC, > 90 % HPV-positive tumors are infected with HPV16. Ten up to 60 % of HPV-positive tumors thus contain extrachromosomal (episomal) virus. In this chapter, causes and consequences of HPV integration are summarized from the literature, with special focus on the site of HPV integration in the cellular genome, and its effect on expression of viral oncogenes (particularly E6 and E7), on human (tumor) gene expression and on deregulation of cell proliferation, apoptosis and cell signaling pathways. Also data on DNA methylation, viral load and clinical outcome in relation to HPV integration are provided.