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

Shuling Ren,Alfredo A Molinolo,Juan Luis Callejas‐Valera ,Takahito Fukusumi,Kathleen M Fisch,Wayne M Koch,Theresa Guo,Akihiro Sakai,J Silvio Gutkind,Guiyin Xu ,Jéssica Luana Dos Santos ,Alexander V Favorov,Sayed Sadat,Pablo Tamayo,Chao Liu,Trey Ideker,Mara Gilardi,Daria A Gaykalova,Zhiyong Wang,Mizuo Ando,Michael Allevato ,Elana J Fertig,Joseph A Califano

doi:10.1038/s41388-020-01431-8

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.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Human papillomavirus (HPV) is a ~7.9 kb, non-enveloped, double-stranded, circular DNA virus that has a specific tropism for squamous epithelium, and persistent infection with oncogenic HPV subtypes is associated with development of cancers of the cervix, oropharynx, vagina, vulva, penis, and nasal cavity
As a part of a TCGA team led by Parfenov et al [6], we found a substantial subset of HPV positive head and neck squamous cell carcinoma (HNSCC) which demonstrated minimal expression of HPV16 E6 and E7 (E6/E7), but dramatic increase in expression of E2, E4, and E5 (E2/ E4/E5) genes, as well as exclusive association of E2/E4/E5 expression with lack of HPV16 integration into the host genome
In order to answer the question of whether significant HPV gene expression subtypes exist in HPV positive cancer, we explored the expression patterns of HPV genes and correlated them with the presence or absence of HPV integration in the host genome

Summary

Introduction

High-risk HPV16 accounts for the largest proportion of HPV positive tumors, with HPV16 associated with 85% of HPV positive head and neck squamous cell carcinoma (HNSCC) and HPV 16 and 18 in 70% of cervical cancers [1, 2]. HPV positive cancers have less somatic alterations and protein expression change comparing with HPV negative cancers [4]. Both cervical squamous cell carcinoma (CESC) and HPV positive HNSCC show an increase rate of PIK3CA mutations in comparison to other solid tumors, and the PIK3CA-AKT-mTOR pathway is the most frequent dysregulated signaling pathway in HNSCC, including >80% of all HPV negative and HPV positive cases [4, 5]

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Results

Conclusion