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

Authors
  • Ren, Shuling1, 2
  • Gaykalova, Daria A.3
  • Guo, Theresa3
  • Favorov, Alexander V.3, 4
  • Fertig, Elana J.3
  • Tamayo, Pablo1
  • Callejas-Valera, Juan Luis1, 5
  • Allevato, Mike1
  • Gilardi, Mara1
  • Santos, Jessica1
  • Fukusumi, Takahito1
  • Sakai, Akihiro1
  • Ando, Mizuo1
  • Sadat, Sayed1
  • Liu, Chao1
  • Xu, Guorong1
  • Fisch, Kathleen M.1
  • Wang, Zhiyong1
  • Molinolo, Alfredo A.1
  • Gutkind, J. Silvio1
  • And 3 more
  • 1 University of California San Diego,
  • 2 Beijing Friendship Hospital, Capital Medical University,
  • 3 Johns Hopkins Medical Institutions,
  • 4 Vavilov Institute of General Genetics, Russian Academy of Sciences,
  • 5 Sanford Research,
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Aug 26, 2020
Volume
39
Issue
40
Pages
6327–6339
Identifiers
DOI: 10.1038/s41388-020-01431-8
PMID: 32848210
PMCID: PMC7529583
Source
PubMed Central
Keywords
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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