Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration

Authors

Keiko Akagi
David E Symer
Medhat Mahmoud
Bo Jiang
Sara Goodwin
Darawalee Wangsa
Zhengke Li
Weihong Xiao
Joe Dan Dunn
Thomas Ried
Kevin R Coombes
Fritz J Sedlazeck
Maura L Gillison

Publication Date

4-3-2023

Journal

Cancer Discovery

Abstract

The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.

Keywords

Humans, Human Papillomavirus Viruses, Papillomavirus Infections, Gene Rearrangement, Oropharyngeal Neoplasms, Clonal Evolution, Virus Integration, Papillomaviridae

Comments

Supplementary Materials

PMID: 36715691