ARTICLE ABSTRACT
Human papillomavirus (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 pointed to integration of virus concatemers into the host genome as a common initiating event in fusion formation. Coexpression 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.
Fusion genes are frequently cancer drivers, but the molecular mechanisms underlying their formation have remained unclear. In this study, we identified HPV integration as the instigator of genomic rearrangements that lead to the formation of FGFR3–TACC3 and other fusion genes. FGFR3–TACC3 expression decreased the ubiquitination and degradation of HPV E6 and E7, furthering the oncogenesis of HPV.
