TY  - JOUR
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
Y1  - 2022/01/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 55 
EP  - 70 
DO  - 10.1101/gr.275911.121 
VL  - 32 
IS  - 1 
UR  - http://genome.cshlp.org/content/32/1/55.abstract 
N2  - 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. 
ER  -