Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas.

Abstract

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.

• Authors: Adeline Morel, Cindy Neuzillet, Maxime Wack, Sonia Lameiras, Sophie Vacher, Marc Deloger, Nicolas Servant, David Veyer, Hélène Péré, Odette Mariani, Sylvain Baulande, Roman Rouzier, Maud Kamal, Elsy El Alam, Emmanuelle Jeannot, Alain Nicolas, Ivan Bièche, Wulfran Cacheux
• Journal: Cancers (Cancers (Basel)) Vol. 11 Issue 12 (Nov 22 2019) ISSN: 2072-6694 [Print] Switzerland
• PMID: 31766658 (Publication Type: Journal Article)