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Open AccessArticle

Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas

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Institut Curie, Pharmacogenomic Unit, 26 rue d’Ulm, 75248 Paris, France
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Institut Curie, Medical Oncology Department, Versailles Saint-Quentin University, 35 rue Dailly, 92210 Saint-Cloud, France
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Département d’Informatique Médicale, Biostatistiques et Santé Publique, Hôpital Européen Georges Pompidou, and Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
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Centre de Recherche des Cordeliers, INSERM UMRS1138, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France
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Institut Curie, Genomics of Excellence (ICGex) Platform, PSL Research University, 26 rue d’Ulm, 75248 Paris CEDEX 05, France
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Institut Curie, Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75248 Paris, France
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Laboratoire de virologie, Hôpital Européen Georges Pompidou, and Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
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Institut Curie, Centre de Ressources Biologiques, 26 rue d’Ulm, 75248 Paris, France
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Institut Curie, Department of Drug Development and Innovation (D3i), Institut Curie Paris & Saint Cloud, 75248 Paris, France
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Institut Curie, Pathology Department, 35 rue Dailly, 92210 Saint-Cloud, France
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Institut Curie, Pathology Department, 26 rue d’Ulm, 75248 Paris, France
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Institut Curie, PSL Research University, CNRS UMR3244, 75248 Paris, France
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INSERM U1016, Université Paris Descartes University, 75006 Paris, France
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Hôpital Privé Pays de Savoie, Service d’oncologie Médicale, 19 Avenue Pierre Mendès France, 74100 Annemasse, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work and serve as co-first authors.
These authors contributed equally to this work and serve as co-last authors.
Cancers 2019, 11(12), 1846; https://doi.org/10.3390/cancers11121846
Received: 21 October 2019 / Revised: 15 November 2019 / Accepted: 19 November 2019 / Published: 22 November 2019
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. View Full-Text
Keywords: anal cancer; HPV; integration; NFIX; prognostic factor anal cancer; HPV; integration; NFIX; prognostic factor
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Morel, A.; Neuzillet, C.; Wack, M.; Lameiras, S.; Vacher, S.; Deloger, M.; Servant, N.; Veyer, D.; Péré, H.; Mariani, O.; Baulande, S.; Rouzier, R.; Kamal, M.; El Alam, E.; Jeannot, E.; Nicolas, A.; Bièche, I.; Cacheux, W. Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas. Cancers 2019, 11, 1846.

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