Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability
- Keiko Akagi1,
- Jingfeng Li1,
- Tatevik R Broutian2,
- Hesed Padilla-Nash3,
- Weihong Xiao1,
- Bo Jiang1,
- James W Rocco4,
- Theodoros N Teknos2,
- Bhavna Kumar2,
- Danny Wangsa3,
- Dandan He1,
- Thomas Ried3,
- David E Symer1,5 and
- Maura L Gillison2
- 1 Ohio State University Comprehensive Cancer Center;
- 2 Ohio State University;
- 3 NIH;
- 4 Massachusetts Eye and Ear Infirmary
- ↵* Corresponding author; email: david.symer{at}osumc.edu
Abstract
Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions and chromosomal translocations. We present a model of 'looping' by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
- Received August 7, 2013.
- Accepted October 17, 2013.
- Published by Cold Spring Harbor Laboratory Press
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