HPV Integration Can Drive the Formation of Virus-Host Extrachromosomal DNA in Tumors

Abstract

Human papillomavirus (HPV)-positive cancer cells contain virus and host DNA and exhibit marked genome instability. In this issue of Cancer Discovery, Akagi and colleagues characterize the remarkably complex landscape of virus-host DNA molecules in HPV-positive cells, providing evidence for diverse integrated and extrachromosomal virus-host hybrid DNAs with the potential to drive clonal evolution. See related article by Akagi et al., p. 910 (4).

Heterocateny in HPV-positive cancers.

Human papillomaviruses establish persistent infections in which the circular DNA genome is maintained as a low copy-number plasmid in infected cells. Accidental integration of the HPV DNA into the host genome is a hallmark of HPV-positive cancers. In this issue of Cancer Discovery, Akagi and colleagues use long-read DNA sequencing of HPV-positive tumors and cell lines to describe heterocateny, the remarkable variation in HPV-host hybrid DNAs that results from successive rounds of DNA recombination, amplification, rearrangement, excision, and reintegration (left). By reconstructing the stepwise events that could account for specific patterns of virus-host hybrid DNA in individual tumors and cell lines, the authors provide compelling evidence for the complex ways in which genomic instability could drive tumor heterogeneity and clonal evolution in HPV-positive cancers (right).