Genomic structures and regulation patterns at HPV integration sites in cervical cancer

Abstract

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression inciswith the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

The benefit of a complete reference genome for cancer structural variant analysis

“…Perhaps more importantly, they can lead to the onset of genome instability and thus the formation of variants or inclusions of viruses (e.g. HPV) (Porter et al 2023; Akagi et al 2023). Annotating these newly assembled regions is challenging, but such annotations are necessary to understand the impact of mutations in these regions.…”