The Drivers, Mechanisms, and Consequences of Genome Instability in HPV-Driven Cancers

Abstract

Human papillomavirus (HPV) is the causative driver of cervical cancer and a contributing risk factor of head and neck cancer and several anogenital cancers. HPV's ability to induce genome instability contributes to its oncogenicity. HPV genes can induce genome instability in several ways, including modulating the cell cycle to favour proliferation, interacting with DNA damage repair pathways to bring high-fidelity repair pathways to viral episomes and away from the host genome, inducing DNA-damaging oxidative stress, and altering the length of telomeres. In addition, the presence of a chronic viral infection can lead to immune responses that also cause genome instability of the infected tissue. The HPV genome can become integrated into the host genome during HPV-induced tumorigenesis. Viral integration requires double-stranded breaks on the DNA; therefore, regions around the integration event are prone to structural alterations and themselves are targets of genome instability. In this review, we present the mechanisms by which HPV-dependent and -independent genome instability is initiated and maintained in HPV-driven cancers, both across the genome and at regions of HPV integration.

Keywords: DNA damage; DNA repair; HPV; cancer; cervical cancer; genome instability; head and neck cancer; mutation; viral integration; virus.

Figure 1

The episomal and integrated forms of the HPV genome: (a) The genes and regulatory regions in the HPV16 episome; (b) An example of the integrated form of HPV16 with breakpoints in the L1 and E2 genes.

Figure 2

The evolution of HPV infection, to cervical intraepithelial neoplasia (CIN), to invasive cervical cancer (ICC). HPV infects basal cells (blue) through microabrasions in the cervical epithelium. Uncontrolled proliferation of the mid-epithelial layers allows the onset of genome instability. After acquiring additional somatic mutations and often HPV integration, the tumor breaks through the basal layer and is graded as an ICC. Created with BioRender.com.

Figure 3

Mechanisms in which E6 and E7 lead to genome instability. The HPV oncoproteins E6 and E7 dysregulate several pathways at both the gene and protein level as a way to increase genome instability in the infected cell, including the cell cycle transition (yellow box), DDR pathways (blue box), generation of oxidative stress (red box), and telomere length alterations (green box). The colour of the box containing the gene name indicates if it is being regulated at the gene or protein level. Created with BioRender.com.

Figure 4

Mechanisms and local consequences of HPV integration in cancer: (a) The looping model proposes that HPV acts as a bridge between two pieces of non-contiguous DNA that have double-stranded DNA breaks in the human genome. The looped bridge can then be successively amplified upon DNA replication; (b) The microhomology model proposes that regions of microhomology between the human genome and HPV mediate integration through DNA repair mistakes in the fork stalling and template switching and microhomology-mediated break-induced replication pathways; (c) The integrated HPV genome can induce types of local rearrangements at the site of integration. Created with BioRender.com.