Human Papilloma Virus Integration Strictly Correlates with Global Genome Instability in Head and Neck Cancer

We applied a combination of whole genome sequencing and whole genome imaging to interrogate the genome structure of HPV-positive oropharyngeal squamous cell carcinomas. We found the virus integrated in the host genome in two thirds of the tumors examined but resided solely extrachromosomally in the other third. Integration of the virus occurred at essentially random sites within the genome and at more than one site in the genome in half the cases of integration. In several cases, integration occurred at the junction between inter- or intra-chromosomal translocations. Focal amplification of the virus and the genomics sequences surrounding it often occurred subsequent to integration, with the number of tandem repeats in the chromosome fully accounting for the increased copy number of the genome sequences flanking the site of integration. In all cases, viral integration correlated with pervasive genome-wide somatic alterations, including multiple insertions, deletions, translocations, inversions and point mutations. Few or no somatic structural variants were present in tumors with only episomal HPV. Our data can best be interpreted by positing that episomal HPV is captured in the host genome following an episode of global genome instability during tumor development. Viral integration and the associated extensive mutation of the genome correlated with more aggressive tumors, suggesting that HPV integration status may inform prognosis.