Immune Signature-Based Subtypes of Cervical Squamous Cell Carcinoma Tightly Associated with Human Papillomavirus Type 16 Expression, Molecular Features, and Clinical Outcome

Substantial heterogeneity exists within cervical cancer that is generally infected by human papillomavirus (HPV). However, the most common histological subtype of cervical cancer, cervical squamous cell carcinoma (CSCC), is poorly characterized regarding the association between its heterogeneity and...

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Bibliographic Details
Published in:Neoplasia (New York, N.Y.) Vol. 21; no. 6; pp. 591 - 601
Main Authors: Lu, Xiaofan, Jiang, Liyun, Zhang, Liya, Zhu, Yue, Hu, Wenjun, Wang, Jiashuo, Ruan, Xinjia, Xu, Zhengbao, Meng, Xiaowei, Gao, Jun, Su, Xiaoping, Yan, Fangrong
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.06.2019
Elsevier
Subjects:
Adult
Carcinoma, Squamous Cell - classification
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - pathology
Carcinoma, Squamous Cell - virology
Class I Phosphatidylinositol 3-Kinases - genetics
DNA Methylation - genetics
F-Box-WD Repeat-Containing Protein 7 - genetics
Female
Gene Expression Regulation, Neoplastic - genetics
Human papillomavirus 16 - genetics
Human papillomavirus 16 - pathogenicity
Humans
Kaplan-Meier Estimate
Keratin-1 - genetics
Middle Aged
Mucin-4 - genetics
Oncogene Proteins, Viral - genetics
Papillomavirus E7 Proteins - genetics
Papillomavirus Infections - genetics
Papillomavirus Infections - immunology
Papillomavirus Infections - pathology
Papillomavirus Infections - virology
Progression-Free Survival
Repressor Proteins - genetics
Signal Transduction - genetics
Uterine Cervical Neoplasms - classification
Uterine Cervical Neoplasms - genetics
Uterine Cervical Neoplasms - pathology
Uterine Cervical Neoplasms - virology
ρ
CGI
CI
GO
GSEA
HR
CESC
FPKM
TCGA
HPV
CSCC
FDR
IC50
ISSN:1476-5586, 1476-5586
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Summary:Substantial heterogeneity exists within cervical cancer that is generally infected by human papillomavirus (HPV). However, the most common histological subtype of cervical cancer, cervical squamous cell carcinoma (CSCC), is poorly characterized regarding the association between its heterogeneity and HPV oncoprotein expression. We filtered out 138 CSCC samples with infection of HPV16 only as the first step; then we compressed HPV16 E6/E7 expression as HPVpca and correlated HPVpca with the immunological profiling of CSCC based on supervised clustering to discover subtypes and to characterize the differences between subgroups in terms of the HPVpca level, pathway activity, epigenetic dysregulation, somatic mutation frequencies, and likelihood of responding to chemo/immunotherapies. Supervised clustering of immune signatures revealed two HPV16 subtypes (namely, HPV16-IMM and HPV16-KRT) that correlated with HPVpca and clinical outcomes. HPV16-KRT is characterized by elevated expression of genes in keratinization, biological oxidation, and Wnt signaling, whereas HPV16-IMM has a strong immune response and mesenchymal features. HPV16-IMM exhibited much more epigenetic silencing and significant mutation at FBXW7, while MUC4 and PIK3CA were mutated frequently for HPV16-KRT. We also imputed that HPV16-IMM is much more sensitive to chemo/immunotherapy than is HPV16-KRT. Our characterization tightly links the expression of HPV16 E6/E7 with biological and clinical outcomes of CSCC, providing valuable molecular-level information that points to decoding heterogeneity. Together, these results shed light on stratifications of CSCC infected by HPV16 and shall help to guide personalized management and treatment of patients.
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ISSN:1476-5586
1476-5586
DOI:10.1016/j.neo.2019.04.003