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

Shuling Ren(Capital Medical University), Daria A. Gaykalova(Johns Hopkins University), Theresa Guo(Johns Hopkins University), Alexander V. Favorov(Johns Hopkins University), Elana J. Fertig(Johns Hopkins University), Pablo Tamayo(University of California San Diego), Juan Luis Callejas‐Valera(University of California San Diego), Mike Allevato(University of California San Diego), Mara Gilardi(University of California San Diego), Jéssica Luana Dos Santos(University of California San Diego), Takahito Fukusumi(University of California San Diego), Akihiro Sakai(University of California San Diego), Mizuo Ando(University of California San Diego), Sayed Sadat(University of California San Diego), Chao Liu(University of California San Diego), Guorong Xu(University of California San Diego), Kathleen M. Fisch(University of California San Diego), Zhiyong Wang(University of California San Diego), Alfredo Molinolo(University of California San Diego), J. Silvio Gutkind(University of California San Diego), Trey Ideker(University of California San Diego), Wayne M. Koch(Johns Hopkins University), Joseph A. Califano(University of California San Diego)
Oncogene
August 26, 2020
10.1038/s41388-020-01431-8
Cited by 98Open Access
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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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