Human papillomavirus genome integration in squamous carcinogenesis: what have next‐generation sequencing studies taught us?

Abstract

Human papillomavirus (HPV) infection is associated with ∼5% of all human cancers, including a range of squamous cell carcinomas. Persistent infection by high-risk HPVs (HRHPVs) is associated with the integration of virus genomes (which are usually stably maintained as extrachromosomal episomes) into host chromosomes. Although HRHPV integration rates differ across human sites of infection, this process appears to be an important event in HPV-associated neoplastic progression, leading to deregulation of virus oncogene expression, host gene expression modulation, and further genomic instability. However, the mechanisms by which HRHPV integration occur and by which the subsequent gene expression changes take place are incompletely understood. The advent of next-generation sequencing (NGS) of both RNA and DNA has allowed powerful interrogation of the association of HRHPVs with human disease, including precise determination of the sites of integration and the genomic rearrangements at integration loci. In turn, these data have indicated that integration occurs through two main mechanisms: looping integration and direct insertion. Improved understanding of integration sites is allowing further investigation of the factors that provide a competitive advantage to some integrants during disease progression. Furthermore, advanced approaches to the generation of genome-wide samples have given novel insights into the three-dimensional interactions within the nucleus, which could act as another layer of epigenetic control of both virus and host transcription. It is hoped that further advances in NGS techniques and analysis will not only allow the examination of further unanswered questions regarding HPV infection, but also direct new approaches to treating HPV-associated human disease.

Human papillomavirus type 18 oncoproteins exert their oncogenicity in esophageal and tongue squamous cell carcinoma cell lines distinctly

“…Other HPV transcripts (E2, E4, E5, E8 and L2) were not detected in all the cell lines. These HPV genome profiling results were consistent with previous reports 36,37 .…”

Rapid Clearance Profile of Plasma Circulating Tumor HPV Type 16 DNA during Chemoradiotherapy Correlates with Disease Control in HPV-Associated Oropharyngeal Cancer

“…2D, >10 TPY or T4 disease). By analyzing matched tumor genomics, we discovered that patients with low pretreatment ctHPV16DNA levels ( 200 copies/mL) had lower tumor HPV copy number and a higher likelihood of HPV integration, which are associated with worse outcomes in OPSCC (5,6,(8)(9)(10)(11)(12)29). In contrast, patients with abundant pretreatment ctHPV16DNA levels (>200 copies/mL plasma) were most likely to have tumors with high copy and episomal HPV, which correlates with favorable prognosis in both cervical cancer and OPSCC (8,9,11,14).…”

Unusual prevalence of high-risk genotypes of human papillomavirus in a group of women with neoplastic lesions and cervical cancer from Central Mexico

“…Regarding the frequency of single or multiple infections according to the lesion grade, we found that the prevalence of single infections was more elevated in low-grade lesions, which can indicate a dissipation effect of a determined genotype to achieve the integration of its genome to the host’s; while the exact mechanisms by which high-risk HPV genotypes succeed in the integration of their genome aren’t completely understood, it has been reported that with the development of next-generation sequencing it is possible to determine the exact integration site and the subsequent genomic rearrangements to it. It has been indicated that such phenomenon takes place through two main mechanisms, loop integration and direct integration, and that a better understanding of the integration sites might allow to understand those factors that give a competitive advantage to certain genotypes during the progression of the disease [29]. However, in our patients with high-grade lesions a synergic effect with even three different genotypes seems to happen, probably as a result of the expression of a higher viral load and even though conflict exists whether if the viral load size or the integration status are determinant factors for the development of high-grade lesions, in a study performed by Manawapat-Klopfer et al with 664 Danish women it was demonstrated that a 10-fold increase of the viral load, in addition to a state of viral genome integration, was significantly associated to the presence of a high-grade lesion [30].…”