Abstract
Oncoviruses cause tremendous global cancer burden. For several DNA tumor viruses, human genome integration is consistently associated with cancer development. However, genomic features associated with tumor viral integration are poorly understood. We sought to define genomic determinants for 1897 loci prone to hosting human papillomavirus (HPV), hepatitis B virus (HBV) or Merkel cell polyomavirus (MCPyV). These were compared to HIV, whose enzyme-mediated integration is well understood. A comprehensive catalog of integration sites was constructed from the literature and experimentally-determined HPV integration sites. Features were scored in eight categories (genes, expression, open chromatin, histone modifications, methylation, protein binding, chromatin segmentation and repeats) and compared to random loci. Random forest models determined loci classification and feature selection. HPV and HBV integrants were not fragile site associated. MCPyV preferred integration near sensory perception genes. Unique signatures of integration-associated predictive genomic features were detected. Importantly, repeats, actively-transcribed regions and histone modifications were common tumor viral integration signatures.
Highlights
Integration into the human genome is central to transposon mutagenesis, gene therapy and viral pathogenesis [1,2,3,4]
Thirty-seven Merkel cell polyomavirus (MCPyV) integration sites were identified in Merkel cell carcinomas (MCCs) (34), lung cancers and a cell line (Table S3)
In this large-scale study, 277 genomic features were assessed around known DNA tumor virus integration sites
Summary
Integration into the human genome is central to transposon mutagenesis, gene therapy and viral pathogenesis [1,2,3,4]. DNA tumor virus integration has been implicated as an early oncogenic event. Hepatitis B virus (HBV) integrates in up to 90% of HBV+ hepatocellular carcinomas (HCCs) [7,8]. Integration may increase cancer risk beyond simple infection. Viral integration can deregulate nearby human oncogenes [14,15], create oncogenic fusion genes [16,17] and contribute to genome instability [8,18]. One potential strategy for reducing cancer risk in infected or early-stage disease patients may be targeted prevention of viral integration. Initial steps will require a better understanding of DNA tumor virus integration
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