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

Shuling Ren; Daria A. Gaykalova; Theresa Guo; Alexander V. Favorov; Elana J. Fertig; Pablo Tamayo; Juan Luis Callejas-Valera; Mike Allevato; Mara Gilardi; Jessica Santos; Takahito Fukusumi; Akihiro Sakai; Mizuo Ando; Sayed Sadat; Chao Liu; Guorong Xu; Kathleen M. Fisch; Zhiyong Wang; Alfredo A. Molinolo; J. Silvio Gutkind; Trey Ideker; Wayne M. Koch; Joseph A. Califano

doi:10.1038/s41388-020-01431-8

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

Shuling Ren, Daria A. Gaykalova, Theresa Guo, Alexander V. Favorov, Elana J. Fertig, Pablo Tamayo, Juan Luis Callejas-Valera, Mike Allevato, Mara Gilardi, Jessica Santos, Takahito Fukusumi, Akihiro Sakai, Mizuo Ando, Sayed Sadat, Chao Liu, Guorong Xu, Kathleen M. Fisch, Zhiyong Wang, Alfredo A. Molinolo, J. Silvio GutkindTrey Ideker, Wayne M. Koch, Joseph A. Califano

School of Medicine

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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.

Original language	English (US)
Pages (from-to)	6327-6339
Number of pages	13
Journal	Oncogene
Volume	39
Issue number	40
DOIs	https://doi.org/10.1038/s41388-020-01431-8
State	Published - Oct 1 2020

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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Ren, S., Gaykalova, D. A., Guo, T., Favorov, A. V., Fertig, E. J., Tamayo, P., Callejas-Valera, J. L., Allevato, M., Gilardi, M., Santos, J., Fukusumi, T., Sakai, A., Ando, M., Sadat, S., Liu, C., Xu, G., Fisch, K. M., Wang, Z., Molinolo, A. A., ... Califano, J. A. (2020). HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers. Oncogene, 39(40), 6327-6339. https://doi.org/10.1038/s41388-020-01431-8

Ren, S, Gaykalova, DA, Guo, T, Favorov, AV , Fertig, EJ, Tamayo, P, Callejas-Valera, JL, Allevato, M, Gilardi, M, Santos, J, Fukusumi, T, Sakai, A, Ando, M, Sadat, S, Liu, C, Xu, G, Fisch, KM, Wang, Z, Molinolo, AA, Gutkind, JS, Ideker, T, Koch, WM & Califano, JA 2020, 'HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers', Oncogene, vol. 39, no. 40, pp. 6327-6339. https://doi.org/10.1038/s41388-020-01431-8

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

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.",

author = "Shuling Ren and Gaykalova, {Daria A.} and Theresa Guo and Favorov, {Alexander V.} and Fertig, {Elana J.} and Pablo Tamayo and Callejas-Valera, {Juan Luis} and Mike Allevato and Mara Gilardi and Jessica Santos and Takahito Fukusumi and Akihiro Sakai and Mizuo Ando and Sayed Sadat and Chao Liu and Guorong Xu and Fisch, {Kathleen M.} and Zhiyong Wang and Molinolo, {Alfredo A.} and Gutkind, {J. Silvio} and Trey Ideker and Koch, {Wayne M.} and Califano, {Joseph A.}",

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doi = "10.1038/s41388-020-01431-8",

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T1 - HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers

AU - Ren, Shuling

AU - Gaykalova, Daria A.

AU - Guo, Theresa

AU - Favorov, Alexander V.

AU - Fertig, Elana J.

AU - Tamayo, Pablo

AU - Callejas-Valera, Juan Luis

AU - Allevato, Mike

AU - Gilardi, Mara

AU - Santos, Jessica

AU - Fukusumi, Takahito

AU - Sakai, Akihiro

AU - Ando, Mizuo

AU - Sadat, Sayed

AU - Liu, Chao

AU - Xu, Guorong

AU - Fisch, Kathleen M.

AU - Wang, Zhiyong

AU - Molinolo, Alfredo A.

AU - Gutkind, J. Silvio

AU - Ideker, Trey

AU - Koch, Wayne M.

AU - Califano, Joseph A.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

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

Abstract

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