Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Automated summary

This study investigates the oncogenic impacts of human papillomavirus (HPV) integration in oropharyngeal cancer. Through whole-genome sequencing analysis of 105 HPV-positive oropharyngeal cancers, virus integration is detected in 77% of cases, with recurrent integration sites near genes involved in epithelial stem cell maintenance and immune evasion. The presence of HPV integrants is associated with increased genomic copy number hyperamplification and focal host genomic instability. The frequency of genes expressed at extreme outlier levels is also significantly increased near integrants. These findings suggest that virus integration can contribute to carcinogenesis in HPV-positive oropharyngeal cancers by disrupting host genome structure and gene expression.