Intratumoral heterogeneity and clonal evolution induced by HPV integration

Akagi, Keiko, Symer, David E, Mahmoud, Medhat, Jiang, Bo, Goodwin, Sara, Wangsa, Darawalee, Li, Zhengke, Xiao, Weihong, Dunn, Joe Dan, Ried, Thomas, Coombes, Kevin R, Sedlazeck, Fritz J, Gillison, Maura L (January 2023) Intratumoral heterogeneity and clonal evolution induced by HPV integration. Cancer Discovery. ISSN 2159-8274

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DOI: 10.1158/2159-8290.CD-22-0900


The 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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > neoplasms
diseases & disorders > viral diseases
diseases & disorders > viral diseases > human papillomavirus
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > insertion/deletion
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service
CSHL labs > McCombie lab
CSHL labs > Goodwin lab
CSHL Cancer Center Program
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 30 January 2023
Date Deposited: 10 Feb 2023 20:57
Last Modified: 09 Feb 2024 13:55
PMCID: PMC10070172

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