Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker.
Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker.
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DOI：
10.1186/s12916-022-02630-8
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发表时间：
2022-11-09
期刊：
影响因子：
9.3
通讯作者：
Li, Shuang
中科院分区：
文献类型：
--
作者：
Zhang, Jianwei;Meng, Silu;Wang, Xiaoyan;Wang, Jun;Fan, Xinran;Sun, Haiying;Ning, Ruoqi;Xiao, Bing;Li, Xiangqin;Jia, Yao;Kong, Dongli;Chen, Ruqi;Wang, Changyu;Ma, Ding;Li, Shuang
子宫颈鳞状细胞癌（SCC）是由越来越高级别的鳞状上皮内病变（锡尔斯）或子宫颈上皮内瘤变（CIN）引起的。本研究的目的是描述宫颈恶性转化的分子变化和识别生物标志物。分析了来自五个公开的微阵列和TCGA-CESC数据集的多维数据。对354例宫颈组织（42例正常，62例CIN 1，26例CIN 2，47例CIN 3和177例SCC）进行免疫组化，以确定所鉴定的生物标志物的潜在诊断和预后价值。我们发现正常上皮和锡尔斯的分子均一性高于SCC。该区域中的基因（例如，3q，12 q13）拷贝数改变或HPV整合的人更容易失去或获得表达。IL-17信号通路在整个疾病进展过程中富集，在晚期IL-17 C下调和Th 17细胞减少。此外，我们确定了AURKA，TOP 2A，RFC 4和CEP 55作为在正常SILs-SCC过渡期间逐渐上调的潜在致病基因。对于检测高级别SIL（HSIL），TOP 2A和RFC 4显示出平衡的敏感性（均为88.2%）和特异性（87.1%和90.1%），具有高AUC（0.88和0.89）。它们单独与p16 INK 4a和Ki-67的组合具有等同的诊断性能。同时，RFC 4表达的增加显著且独立地预测了多机构SCC患者队列的良好结局。我们对基因表达谱的综合研究已经确定了宫颈癌发生过程中失调的基因和生物学过程。RFC 4被认为是一种新的替代生物标志物，用于确定HSIL和HSIL+，以及SCC的独立预后生物标志物。在线版本包含补充材料，可通过10.1186/s12916-022-02630-8获得。
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. 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. 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. 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. The online version contains supplementary material available at 10.1186/s12916-022-02630-8.
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