RT Journal
A1 Symer, David E.
A1 Akagi, Keiko
A1 Geiger, Heather M.
A1 Song, Yang
A1 Li, Gaiyun
A1 Emde, Anne-Katrin
A1 Xiao, Weihong
A1 Jiang, Bo
A1 Corvelo, André
A1 Toussaint, Nora C.
A1 Li, Jingfeng
A1 Agrawal, Amit
A1 Ozer, Enver
A1 El-Naggar, Adel K.
A1 Du, Zoe
A1 Shewale, Jitesh B.
A1 Stache-Crain, Birgit
A1 Zucker, Mark
A1 Robine, Nicolas
A1 Coombes, Kevin R.
A1 Gillison, Maura L.
T1 Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers
JF Genome Research 
JO Genome Research 
YR 2022 
FD January 01 
VO 32 
IS 1 
SP 55 
OP 70 
DO 10.1101/gr.275911.121 
UL http://genome.cshlp.org/content/32/1/55.abstract 
AB 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.