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.
Highlights
Anal squamous cell carcinoma (ASCC) accounts for about 2.5% of all gastrointestinal malignancies [1]
Fifteen (16.1%) patients were treated by upfront surgery, 63 (67.7%) patients were treated by CRT, and 22 (23.7%) received RT alone or in addition to surgery
Seventy-two (86.7%) of the 83 patients treated by RT or CRT achieved a complete tumor response (CR)
Summary
Anal squamous cell carcinoma (ASCC) accounts for about 2.5% of all gastrointestinal malignancies [1]. It is more frequent in women and in older patients (age ≥ 65). ASCC is associated with human papillomavirus (HPV) infection. Anal intercourse and a high lifetime number of sexual partners increase the risk of persistent HPV infection and subsequent anal intraepithelial neoplasia and ASCC [7]. Other risk factors for ASCC include immunosuppression induced by human immunodeficiency virus (HIV) infection or the use of immunosuppressants after solid organ transplantation, hematologic malignancies, as well as a history of other HPV-related cancers, autoimmune disorders, low socio-economic status, and smoking [7]
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