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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Cervical Cancer | Research article

Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker

Authors: Jianwei Zhang, Silu Meng, Xiaoyan Wang, Jun Wang, Xinran Fan, Haiying Sun, Ruoqi Ning, Bing Xiao, Xiangqin Li, Yao Jia, Dongli Kong, Ruqi Chen, Changyu Wang, Ding Ma, Shuang Li

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Cervical squamous cell carcinoma (SCC) is known to arise through increasingly higher-grade squamous intraepithelial lesions (SILs) or cervical intraepithelial neoplasias (CINs). This study aimed to describe sequential molecular changes and identify biomarkers in cervical malignant transformation.

Methods

Multidimensional data from five publicly available microarray and TCGA-CESC datasets were analyzed. Immunohistochemistry was carried out on 354 cervical tissues (42 normal, 62 CIN1, 26 CIN2, 47 CIN3, and 177 SCC) to determine the potential diagnostic and prognostic value of identified biomarkers.

Results

We demonstrated that normal epithelium and SILs presented higher molecular homogeneity than SCC. Genes in the region (e.g., 3q, 12q13) with copy number alteration or HPV integration were more likely to lose or gain expression. The IL-17 signaling pathway was enriched throughout disease progression with downregulation of IL17C and decreased Th17 cells at late stage. Furthermore, we identified AURKA, TOP2A, RFC4, and CEP55 as potential causative genes gradually upregulated during the normal-SILs-SCC transition. For detecting high-grade SIL (HSIL), TOP2A and RFC4 showed balanced sensitivity (both 88.2%) and specificity (87.1 and 90.1%), with high AUC (0.88 and 0.89). They had equivalent diagnostic performance alone to the combination of p16INK4a and Ki-67. Meanwhile, increased expression of RFC4 significantly and independently predicted favorable outcomes in multi-institutional cohorts of SCC patients.

Conclusions

Our comprehensive study of gene expression profiling has identified dysregulated genes and biological processes during cervical carcinogenesis. RFC4 is proposed as a novel surrogate biomarker for determining HSIL and HSIL+, and an independent prognostic biomarker for SCC.
Appendix
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Metadata
Title
Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker
Authors
Jianwei Zhang
Silu Meng
Xiaoyan Wang
Jun Wang
Xinran Fan
Haiying Sun
Ruoqi Ning
Bing Xiao
Xiangqin Li
Yao Jia
Dongli Kong
Ruqi Chen
Changyu Wang
Ding Ma
Shuang Li
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02630-8

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