Human Papillomavirus Integration Strictly Correlates with Global Genome Instability in Head and Neck Cancer

Abstract

Human papillomavirus (HPV)-positive head and neck cancers, predominantly oropharyngeal squamous cell carcinoma (OPSCC), exhibit epidemiologic, clinical, and molecular characteristics distinct from those OPSCCs lacking HPV. We applied a combination of whole-genome sequencing and optical genome mapping to interrogate the genome structure of HPV-positive OPSCCs. We found that the virus had integrated in the host genome in two thirds of the tumors examined but resided solely extrachromosomally in the other third. Integration of the virus occurred at essentially random sites within the genome. Focal amplification of the virus and the genomic sequences surrounding it often occurred subsequent to integration, with the number of tandem repeats in the chromosome accounting for the increased copy number of the genome sequences flanking the site of integration. In all cases, viral integration correlated with pervasive genome-wide somatic alterations at sites distinct from that of viral integration and comprised multiple insertions, deletions, translocations, inversions, and point mutations. Few or no somatic mutations were present in tumors with only episomal HPV. Our data could be interpreted by positing that episomal HPV is captured in the host genome following an episode of global genome instability during tumor development. Viral integration correlated with higher grade tumors, which may be explained by the associated extensive mutation of the genome and suggests that HPV integration status may inform prognosis. Implications: Our results indicate that HPV integration in head and neck cancer correlates with extensive pangenomic structural variation, which may have prognostic implications.

Direct Comparison of HPV16 Viral Genomic Integration, Copy Loss, and Structural Variants in Oropharyngeal and Uterine Cervical Cancers Reveal Distinct Relationships to E2 Disruption and Somatic Alteration

“…Similarly, one could consider if the molecular process of integration is variable between the two diseases, and indeed, at least three structural classes of integration sites have been identified: single viral genomic insertions (Type I), insertions of tandem viral repeats (Type II), and tandem repeats of hybrid viral–human DNA (Type III) [ 72 ]. Unfortunately, without long reads or optical techniques [ 72 , 85 ], it is impossible to distinguish these types, as in our data. However, integrations were commonly found to be quite complex in both OPSCC and UCSCC, with four or more human–viral genomic junctions; these do not fit well into any of the described models in the literature.…”

“…Maybe not surprisingly, APOBEC3A (A3A) protein expression has been strongly correlated with increased double-strand breaks and HPV viral integration [ 84 ]. Others have shown that integration also directly correlates with genomic instability [ 85 ]. Whether differences in DNA damage repair and global genomic instability between UCSCC and OPSCC may explain the differential rates of integration is unknown but merits additional focused analysis.…”

Integration and viral oncogene expression of human papillomavirus type 16 in oropharyngeal squamous cell carcinoma and gastric cancer

“…19 In the same study, tumors with integrated HPV were correlated with higher pathology grade. 19 Given the wide range of HPV assays used in the literature, it is necessary to develop a platform that combines available HPV assays that are able to identify HPV genotypes, episomal or integration status, and the expression of viral oncogenes simultaneously. Accordingly, in the present study, we applied multiple methods (Figure 1) to detect HPV status in GC and OPSCC.…”

Development of a Novel Molecular Test for Determining HPV Integration Status in HPV-Positive Oropharynx Cancers

“…2 This viral-mediated disease likely coexists with the host in 2 distinct states: (1) episomal, or outside the host genome, and (2) integrated into the genome itself. Understanding the integration status of the virus in OPSCC could aid in determining future treatment paradigms, 3 but first a rapid, lowcost assay for detecting integration is needed to aid in stratification of patients to different therapy modalities, should integration induce more aggressive disease. This diagnostic study de-scribes the development of an assay for HPV-driven cancers of the oropharynx and the role viral integration could play in the process.…”

“…To our knowledge, there have been only around 20 cases reported in the literature so far, with more than half of them being found in the head and neck region. [1][2][3][4][5] Epstein-Barr virus-positivity is commonly seen in plasmablastic lymphoma (PBL), which is a distinctive disease in patients with human immunodeficiency virus (HIV) recognized by the World Health Organization classification system. 6 Given that PBL usually has a much poorer prognosis even with aggressive chemoradiation therapy, it is important to distinguish these 2 entities although the clinicopathologic features between the 2 often overlap.…”