Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration

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dc.citation.firstpage910en_US
dc.citation.issueNumber4en_US
dc.citation.journalTitleCancer Discoveryen_US
dc.citation.lastpage927en_US
dc.citation.volumeNumber13en_US
dc.contributor.authorAkagi, Keikoen_US
dc.contributor.authorSymer, David E.en_US
dc.contributor.authorMahmoud, Medhaten_US
dc.contributor.authorJiang, Boen_US
dc.contributor.authorGoodwin, Saraen_US
dc.contributor.authorWangsa, Darawaleeen_US
dc.contributor.authorLi, Zhengkeen_US
dc.contributor.authorXiao, Weihongen_US
dc.contributor.authorDan Dunn, Joeen_US
dc.contributor.authorRied, Thomasen_US
dc.contributor.authorCoombes, Kevin R.en_US
dc.contributor.authorSedlazeck, Fritz J.en_US
dc.contributor.authorGillison, Maura L.en_US
dc.date.accessioned2023-04-25T14:47:45Zen_US
dc.date.available2023-04-25T14:47:45Zen_US
dc.date.issued2023en_US
dc.description.abstractThe human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, “heterocateny,” characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus–host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.Long-read sequencing of HPV-positive cancers revealed “heterocateny,” a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution.See related commentary by McBride and White, p. 814.This article is highlighted in the In This Issue feature, p. 799en_US
dc.identifier.citationAkagi, Keiko, Symer, David E., Mahmoud, Medhat, et al.. "Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration." <i>Cancer Discovery,</i> 13, no. 4 (2023) AACR: 910-927. https://doi.org/10.1158/2159-8290.CD-22-0900.en_US
dc.identifier.digital910en_US
dc.identifier.doihttps://doi.org/10.1158/2159-8290.CD-22-0900en_US
dc.identifier.urihttps://hdl.handle.net/1911/114817en_US
dc.language.isoengen_US
dc.publisherAACRen_US
dc.rightsThis open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.en_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleIntratumoral Heterogeneity and Clonal Evolution Induced by HPV Integrationen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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