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Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas
The role of human papillomavirus (HPV) in anal squamous cell carcinoma (ASCC) carcinogenesis has been clearly established, involving the expression of viral oncoproteins and optional viral DNA integration into the host genome. In this article, we describe the various mechanisms and sites of HPV DNA...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966520/ https://www.ncbi.nlm.nih.gov/pubmed/31766658 http://dx.doi.org/10.3390/cancers11121846 |
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author | Morel, Adeline Neuzillet, Cindy Wack, Maxime Lameiras, Sonia Vacher, Sophie Deloger, Marc Servant, Nicolas Veyer, David Péré, Hélène Mariani, Odette Baulande, Sylvain Rouzier, Roman Kamal, Maud El Alam, Elsy Jeannot, Emmanuelle Nicolas, Alain Bièche, Ivan Cacheux, Wulfran |
author_facet | Morel, Adeline Neuzillet, Cindy Wack, Maxime Lameiras, Sonia Vacher, Sophie Deloger, Marc Servant, Nicolas Veyer, David Péré, Hélène Mariani, Odette Baulande, Sylvain Rouzier, Roman Kamal, Maud El Alam, Elsy Jeannot, Emmanuelle Nicolas, Alain Bièche, Ivan Cacheux, Wulfran |
author_sort | Morel, Adeline |
collection | PubMed |
description | The role of human papillomavirus (HPV) in anal squamous cell carcinoma (ASCC) carcinogenesis has been clearly established, involving the expression of viral oncoproteins and optional viral DNA integration into the host genome. In this article, we describe the various mechanisms and sites of HPV DNA insertion and assess their prognostic and predictive value in a large series of patients with HPV-positive ASCC with long-term follow-up. We retrospectively analyzed 96 tumor samples from 93 HPV-positive ASCC patients using the Capture-HPV method followed by Next-Generation Sequencing, allowing determination of HPV genotype and identification of the mechanisms and sites of viral genome integration. We identified five different mechanistic signatures of HPV insertions. The distribution of HPV signatures differed from that previously described in HPV-positive cervical carcinoma (p < 0.001). In ASCC samples, the HPV genome more frequently remained in episomal form (45.2%). The most common signature of HPV insertion was MJ-SC (26.9%), i.e., HPV–chromosomal junctions scattered at different loci. Functionally, HPV integration signatures were not associated with survival or response to treatment, but were associated with viral load (p = 0.022) and PIK3CA mutation (p = 0.0069). High viral load was associated with longer survival in both univariate (p = 0.044) and multivariate (p = 0.011) analyses. Finally, HPV integration occurred on most human chromosomes, but intragenic integration into the NFIX gene was recurrently observed (n = 4/51 tumors). Overall, the distribution of mechanistic signatures of HPV insertions in ASCC was different from that observed in cervical carcinoma and was associated with viral load and PIK3CA mutation. We confirmed recurrent targeting of NFIX by HPV integration, suggesting a role for this gene in ASCC carcinogenesis. |
format | Online Article Text |
id | pubmed-6966520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69665202020-01-27 Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas Morel, Adeline Neuzillet, Cindy Wack, Maxime Lameiras, Sonia Vacher, Sophie Deloger, Marc Servant, Nicolas Veyer, David Péré, Hélène Mariani, Odette Baulande, Sylvain Rouzier, Roman Kamal, Maud El Alam, Elsy Jeannot, Emmanuelle Nicolas, Alain Bièche, Ivan Cacheux, Wulfran Cancers (Basel) Article The role of human papillomavirus (HPV) in anal squamous cell carcinoma (ASCC) carcinogenesis has been clearly established, involving the expression of viral oncoproteins and optional viral DNA integration into the host genome. In this article, we describe the various mechanisms and sites of HPV DNA insertion and assess their prognostic and predictive value in a large series of patients with HPV-positive ASCC with long-term follow-up. We retrospectively analyzed 96 tumor samples from 93 HPV-positive ASCC patients using the Capture-HPV method followed by Next-Generation Sequencing, allowing determination of HPV genotype and identification of the mechanisms and sites of viral genome integration. We identified five different mechanistic signatures of HPV insertions. The distribution of HPV signatures differed from that previously described in HPV-positive cervical carcinoma (p < 0.001). In ASCC samples, the HPV genome more frequently remained in episomal form (45.2%). The most common signature of HPV insertion was MJ-SC (26.9%), i.e., HPV–chromosomal junctions scattered at different loci. Functionally, HPV integration signatures were not associated with survival or response to treatment, but were associated with viral load (p = 0.022) and PIK3CA mutation (p = 0.0069). High viral load was associated with longer survival in both univariate (p = 0.044) and multivariate (p = 0.011) analyses. Finally, HPV integration occurred on most human chromosomes, but intragenic integration into the NFIX gene was recurrently observed (n = 4/51 tumors). Overall, the distribution of mechanistic signatures of HPV insertions in ASCC was different from that observed in cervical carcinoma and was associated with viral load and PIK3CA mutation. We confirmed recurrent targeting of NFIX by HPV integration, suggesting a role for this gene in ASCC carcinogenesis. MDPI 2019-11-22 /pmc/articles/PMC6966520/ /pubmed/31766658 http://dx.doi.org/10.3390/cancers11121846 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Morel, Adeline Neuzillet, Cindy Wack, Maxime Lameiras, Sonia Vacher, Sophie Deloger, Marc Servant, Nicolas Veyer, David Péré, Hélène Mariani, Odette Baulande, Sylvain Rouzier, Roman Kamal, Maud El Alam, Elsy Jeannot, Emmanuelle Nicolas, Alain Bièche, Ivan Cacheux, Wulfran Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title | Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title_full | Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title_fullStr | Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title_full_unstemmed | Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title_short | Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas |
title_sort | mechanistic signatures of human papillomavirus insertions in anal squamous cell carcinomas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966520/ https://www.ncbi.nlm.nih.gov/pubmed/31766658 http://dx.doi.org/10.3390/cancers11121846 |
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