Research

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

    • 1Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
    • 2Viral Oncology Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
    • 3Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA;
    • 4Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA;
    • 5Cancer Genomics Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20814, USA;
    • 6Center for Cancer Research and Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
    • 7Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02115, USA;
    • 8Department of Otolaryngology–Head and Neck Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210, USA;
    • 9Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA
Published November 7, 2013. Vol 24 Issue 2, pp. 185-199. https://doi.org/10.1101/gr.164806.113
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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.

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