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HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers.

Authors
  • Ren, Shuling1, 2
  • Gaykalova, Daria A3
  • Guo, Theresa3
  • Favorov, Alexander V4, 5
  • Fertig, Elana J4
  • Tamayo, Pablo6
  • Callejas-Valera, Juan Luis1, 7
  • Allevato, Mike1
  • Gilardi, Mara1
  • Santos, Jessica1
  • Fukusumi, Takahito1
  • Sakai, Akihiro1
  • Ando, Mizuo1
  • Sadat, Sayed1
  • Liu, Chao1
  • Xu, Guorong6
  • Fisch, Kathleen M6
  • Wang, Zhiyong1
  • Molinolo, Alfredo A1
  • Gutkind, J Silvio1
  • And 3 more
  • 1 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
  • 2 Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China. , (China)
  • 3 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
  • 4 Division of Oncology Biostatistics, Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
  • 5 Laboratory of Systems Biology and Computational Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
  • 6 Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 7 Cancer Biology and Immunotherapies group, Sanford Research, Sioux Falls, SD, USA.
  • 8 Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. [email protected]
  • 9 Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California San Diego, La Jolla, CA, USA. [email protected]
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Oct 01, 2020
Volume
39
Issue
40
Pages
6327–6339
Identifiers
DOI: 10.1038/s41388-020-01431-8
PMID: 32848210
Source
Medline
Language
English
License
Unknown

Abstract

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

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