Rearrangements of viral and human genomes at human papillomavirus integration events and their allele-specific impacts on cancer genome regulation
- Vanessa L. Porter1,2,3,
- Michelle Ng1,3,
- Kieran O'Neill1,
- Signe MacLennan1,2,3,
- Richard D. Corbett1,
- Luka Culibrk1,4,
- Zeid Hamadeh5,6,
- Marissa Iden7,8,
- Rachel Schmidt7,8,
- Shirng-Wern Tsaih7,8,
- Carolyn Nakisige9,
- Martin Origa9,
- Jackson Orem9,
- Glenn Chang1,10,
- Jeremy Fan1,4,
- Ka Ming Nip1,4,
- Vahid Akbari1,2,
- Simon K. Chan1,
- James Hopkins1,
- Richard A. Moore1,
- Eric Chuah1,
- Karen L. Mungall1,
- Andrew J. Mungall1,
- Inanc Birol1,2,
- Steven J.M. Jones1,2,
- Janet S. Rader7,8 and
- Marco A. Marra1,2,3
- 1Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia V5Z 4S6, Canada;
- 2Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;
- 3Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;
- 4Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia V6T 1Z2, Canada;
- 5Cytogenomics Laboratory, Vancouver General Hospital, Vancouver, British Columbia V5Z 1N1, Canada;
- 6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z7, Canada;
- 7Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA;
- 8Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin 53226, USA;
- 9Uganda Cancer Institute, Kampala, Uganda;
- 10Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, British Columbia V6T 1Z2, Canada
Abstract
Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer. To resolve genome dysregulation associated with HPV integration, we performed Oxford Nanopore Technologies long-read sequencing on 72 cervical cancer genomes from a Ugandan data set that was previously characterized using short-read sequencing. We find recurrent structural rearrangement patterns at HPV integration events, which we categorize as del(etion)-like, dup(lication)-like, translocation, multi-breakpoint, or repeat region integrations. Integrations involving amplified HPV–human concatemers, particularly multi-breakpoint events, frequently harbor heterogeneous forms and copy numbers of the viral genome. Transcriptionally active integrants are characterized by unmethylated regions in both the viral and human genomes downstream from the viral transcription start site, resulting in HPV–human fusion transcripts. In contrast, integrants without evidence of expression lack consistent methylation patterns. Furthermore, whereas transcriptional dysregulation is limited to genes within 200 kb of an HPV integrant, dysregulation of the human epigenome in the form of allelic differentially methylated regions affects megabase expanses of the genome, irrespective of the integrant's transcriptional status. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279041.124.
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Freely available online through the Genome Research Open Access option.
- Received January 31, 2024.
- Accepted November 19, 2024.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
