Faculty, Staff and Student Publications

Language

English

Publication Date

9-4-2025

Journal

Cancer Discovery

DOI

10.1158/2159-8290.CD-24-1535

PMID

40358390

PMCID

PMC12315581

PubMedCentral® Posted Date

3-4-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of E6 and E7, thereby increasing oncoprotein abundance. We conclude that expression of HPV16 oncoproteins and host gene fusions generated from HPV integration sites can be sufficient for cancer development.

Keywords

Humans, Oropharyngeal Neoplasms, Animals, Mice, Papillomavirus Infections, Receptor, Fibroblast Growth Factor, Type 3, Virus Integration, Oncogene Proteins, Viral, Human papillomavirus 16, Papillomavirus E7 Proteins, Ubiquitination, Repressor Proteins, Human Papillomavirus Viruses, Microtubule-Associated Proteins, human papillomavirus, head and neck squamous cell carcinoma, long-read sequencing, genomic structural variation, heterocateny, integration, oropharynx

Published Open-Access

yes

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