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bioRxiv · 10.1101/2021.02.11.430847

SearcHPV: a novel approach to identify and assemble human papillomavirus-host genomic integration events in cancer

Pinatti, L. M.·Gu, W.·Wang, Y.·El Hossiny, A.·Bhangale, A. D.·Brummel, C. V.·Carey, T. E.·Mills, R. E.·Brenner, J. C.
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Abstract

BackgroundHuman papillomavirus (HPV) is a well-established driver of malignant transformation in a number of sites including head and neck, cervical, vulvar, anorectal and penile squamous cell carcinomas; however, the impact of HPV integration into the host human genome on this process remains largely unresolved. This is due to the technical challenge of identifying HPV integration sites, which includes limitations of existing informatics approaches to discover viral-host breakpoints from low read coverage sequencing data. MethodsTo overcome this limitation, we developed a new HPV detection pipeline called SearcHPV based on targeted capture technology and applied the algorithm to targeted capture data. We performed an integrated analysis of SearcHPV-defined breakpoints with genome-wide linked read sequencing to identify potential HPV-related structural variations. ResultsThrough analysis of HPV+ models, we show that SearcHPV detects HPV-host integration sites with a higher sensitivity and specificity than two other commonly used HPV detection callers. SearcHPV uncovered HPV integration sites adjacent to known cancer-related genes including TP63 and MYC, as well as near regions of large structural variation. We further validated the junction contig assembly feature of SearcHPV, which helped to accurately identify viral-host junction breakpoint sequences. We found that viral integration occurred through a variety of DNA repair mechanisms including non-homologous end joining, alternative end joining and microhomology mediated repair. ConclusionsIn summary, we show that SearcHPV is a new optimized tool for the accurate detection of HPV-human integration sites from targeted capture DNA sequencing data.

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Pinatti, L. M., Gu, W., Wang, Y., El Hossiny, A., Bhangale, A. D., Brummel, C. V., Carey, T. E., Mills, R. E., Brenner, J. C.. 2021-02-15. SearcHPV: a novel approach to identify and assemble human papillomavirus-host genomic integration events in cancer. https://doi.org/10.1101/2021.02.11.430847

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