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Updated: May 14, 2025

RNAscope for In situ Detection of Transcriptionally Active Human Papillomavirus in Head and Neck Squamous Cell Carcinoma
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Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions in Oropharyngeal Cancers

Nusrat Khan1, Keiko Akagi1, Shiming Jiang1

  • 1Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer Discovery
|May 13, 2025
PubMed

Insights

Human papillomavirus (HPV) integration can cause gene fusions, like FGFR3-TACC3, which, along with HPV oncoproteins, drive oropharyngeal cancer development. This highlights a key mechanism in HPV-driven carcinogenesis.

Area of Science:

  • Oncology
  • Genomics
  • Virology

Background:

  • Human papillomavirus (HPV) integration into the host genome disrupts cellular processes, but its direct role in cancer development is not fully understood.
  • Genomic alterations and gene fusions adjacent to HPV integration sites have been observed in oropharyngeal cancers.

Purpose of the Study:

  • To investigate whether HPV integration-induced host gene fusions contribute to cancer development.
  • To elucidate the molecular mechanisms by which HPV oncoproteins and host gene fusions interact to promote tumorigenesis.

Main Methods:

  • Genomic analyses of oropharyngeal cancers to identify host fusion genes.
  • Evolutionary modeling to understand the origins of fusion gene formation.
  • Mouse models (xenograft and syngeneic) to assess the oncogenic potential of HPV oncoproteins and FGFR3-TACC3.
  • Analysis of oncoprotein stability and transcriptional changes.

Main Results:

  • Recurrent FGFR3-TACC3 fusions were identified adjacent to HPV integration sites in oropharyngeal cancers.
  • Integration of viral concatemers was implicated as an initiating event in fusion formation.
  • Co-expression of HPV16 E6/E7 oncoproteins and FGFR3-TACC3, but not individually, was sufficient for tumor development in mouse models.
  • FGFR3-TACC3 expression stabilized HPV oncoproteins by reducing their degradation, increasing their abundance.
  • Tumorigenesis was associated with unique transcriptional programs.

Conclusions:

  • HPV integration leading to host gene fusions, such as FGFR3-TACC3, plays a significant role in oropharyngeal cancer development.
  • The combined expression of HPV oncoproteins and specific host gene fusions is sufficient to initiate and drive cancer.
  • Understanding these mechanisms provides insights into HPV-driven carcinogenesis and potential therapeutic targets.

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