Human papillomavirus integration induces oncogenic host gene fusions in oropharyngeal cancers
Menée à partir de l'analyse génomique de tumeurs oropharyngées et à l'aide de modèles murins, cette étude démontre que l'expression conjointe des oncoprotéines E6/E7 et du gène de fusion FGFR3-TACC3, généré par l'intégration de l'ADN du papillomavirus humain HPV16 dans le génome de l'hôte, peut être suffisante pour le développement tumoral
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.
Cancer Discovery , résumé, 2025