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Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift?

Morgan, Iain, DiNardo, Laurence, Windle, Brad·2017·Viruses
DOI 10.3390/v9080208PMC PMC5580465
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Abstract

Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where the viral genome remains episomal, one where the viral genome integrates into the host genome and a third where there is a mixture of both integrated and episomal HPV genomes. Our recent work suggests that this third category has been mischaracterized as having integrated HPV genomes; evidence indicates that this category consists of virus–human hybrid episomes. Most of these hybrid episomes are consistent with being maintained by replication from HPV origin. We discuss our evidence to support this new paradigm, how such genomes can arise, and more importantly the implications for the clinical management of HPV positive head and neck cancers following accurate determination of the viral genome status.

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Figure 1 Mechanisms for formation of viral–human hybrid episomes. In (A), a human papillomavirus 16 (HPV16) dimer has broken and integrated into the host genome, losing a part of one of the viral genomes as often happens during integration. E1 and E2 can still be expressed from the intact HPV genome and therefore the potential to initiate replication from the viral origins is retained; this initiation is not restricted to once per cell cycle therefore repeated initiation would form an “onion skin” replication bubble. This would create stress on the host genome resulting in double strand breaks promoting excision from the host genome. This viral–human hybrid DNA could then be ligated to form an episome. In (B), the breaks occur in the host genome flanking the integrated viral genome (the green arrows) and ligation occurs to form an episome that consists of the viral genome with two flanking regions of human DNA. In (C) the breaks in the DNA occur in the viral genome and in flanking human DNA (orange arrows) and ligation occurs to form a viral–human hybrid episome that consists of the viral genome with one flanking region of human DNA. LCR = long control region.
Figure 1 Mechanisms for formation of viral–human hybrid episomes. In (A), a human papillomavirus 16 (HPV16) dimer has broken and integrated into the host genome, losing a part of one of the viral genomes as often happens during integration. E1 and E2 can still be expressed from the intact HPV genome and therefore the potential to initiate replication from the viral origins is retained; this initiation is not restricted to once per cell cycle therefore repeated initiation would form an “onion skin” replication bubble. This would create stress on the host genome resulting in double strand breaks promoting excision from the host genome. This viral–human hybrid DNA could then be ligated to form an episome. In (B), the breaks occur in the host genome flanking the integrated viral genome (the green arrows) and ligation occurs to form an episome that consists of the viral genome with two flanking regions of human DNA. In (C) the breaks in the DNA occur in the viral genome and in flanking human DNA (orange arrows) and ligation occurs to form a viral–human hybrid episome that consists of the viral genome with one flanking region of human DNA. LCR = long control region.CC BY · PubMed Central
Figure 2 The genomic status of HPV16 in head and neck cancers. (A) The HPV genome has broken and become integrated permanently into the host; (B) The HPV genome remains as an episome; (C) An HPV dimer (or multimer) has integrated and been excised along with human DNA and ligated together to form a viral–human hybrid DNA episome (see Figure 1); (D) Previously the viral–human hybrid episome tumors would have been assigned as a mixed tumor that contains both integrated and episomal viral genomes. The box below describes various tests that have been used to characterize the status of the HPV genome in cancers; Y = yes, N = no. It is notable that all of these tests carried out together can differentiate between integrated and episomal tumors, but they do not allow differentiation between whether the viral genome exists as an episomal viral–human hybrid or as a mixed tumor. We propose that these tumors have viral–human hybrid episomes following our analysis of The Cancer Genome Atlas data; so-called mixed tumors, if they exist at all in head and neck cancers, are rare. See the text for details.
Figure 2 The genomic status of HPV16 in head and neck cancers. (A) The HPV genome has broken and become integrated permanently into the host; (B) The HPV genome remains as an episome; (C) An HPV dimer (or multimer) has integrated and been excised along with human DNA and ligated together to form a viral–human hybrid DNA episome (see Figure 1); (D) Previously the viral–human hybrid episome tumors would have been assigned as a mixed tumor that contains both integrated and episomal viral genomes. The box below describes various tests that have been used to characterize the status of the HPV genome in cancers; Y = yes, N = no. It is notable that all of these tests carried out together can differentiate between integrated and episomal tumors, but they do not allow differentiation between whether the viral genome exists as an episomal viral–human hybrid or as a mixed tumor. We propose that these tumors have viral–human hybrid episomes following our analysis of The Cancer Genome Atlas data; so-called mixed tumors, if they exist at all in head and neck cancers, are rare. See the text for details.CC BY · PubMed Central

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Cited by

See all 65

Metadata

Authors
Morgan, I., DiNardo, L., & Windle, B.
Venue
Viruses
Publisher
MDPI AG
Published
2017-08-03
Volume
9
Issue
8
Pages
208
ISSN
1999-4915
DOI
10.3390/v9080208
PMC
PMC5580465
Cited by
65
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute for Dental and Craniofacial Research (R03DE026230-01)
  • National Cancer Institute (P30 CA016059)

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift? https://app.cochat.ai/papers/10.3390/v9080208
The paper
Morgan, I., DiNardo, L., & Windle, B. (2017). Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift? Viruses. https://doi.org/10.3390/v9080208