Immune Signature-Based Subtypes of Cervical Squamous Cell Carcinoma Tightly Associated with Human Papillomavirus Type 16 Expression, Molecular Features, and Clinical Outcome1

Autor: Lu, Xiaofan, Jiang, Liyun, Zhang, Liya, Zhu, Yue, Hu, Wenjun, Wang, Jiashuo, Ruan, Xinjia, Xu, Zhengbao, Meng, Xiaowei, Gao, Jun, Su, Xiaoping, Yan, Fangrong
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Adult
Original article
F-Box-WD Repeat-Containing Protein 7
FDR
false discovery rate
Class I Phosphatidylinositol 3-Kinases
viruses
Papillomavirus E7 Proteins
Uterine Cervical Neoplasms
HPV
human papillomavirus
Kaplan-Meier Estimate
GSEA
gene set enrichment analysis
IC50
half-maximal inhibitory concentration
GO
Gene Ontology
Humans
neoplasms
Human papillomavirus 16
integumentary system
Mucin-4
Papillomavirus Infections
virus diseases
CESC
cervical squamous cell carcinoma and endocervical adenocarcinoma
Oncogene Proteins
Viral
DNA Methylation
Middle Aged
HR
hazard ratio
female genital diseases and pregnancy complications
Progression-Free Survival
CI
confidence interval
Gene Expression Regulation
Neoplastic
Repressor Proteins
FPKM
fragments per kilobase of nonoverlapped exon per million fragments mapped
Carcinoma
Squamous Cell
TCGA
The Cancer Genome Atlas
CGI
CpG island
Female
CSCC
cervical squamous cell carcinoma
ρ
Pearson correlation coefficient
Keratin-1
Signal Transduction
Zdroj: Neoplasia (New York, N.Y.)
ISSN: 1476-5586
1522-8002
Popis: 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.
Databáze: OpenAIRE
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