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.
Objective To investigate the detailed procedure and efficacy of multiple targeting CO2 laser ablation (MTLA-CO2) for the treatment of vaginal intraepithelial neoplasia (VaIN) and to obtain a stably high cure rate and low complication incidence. Design Patients with VaIN were recruited and received MTLA. After follow-up, we aimed to find the risk factors affecting the efficacy. Setting Obstetrics & Gynecological outpatients’ department of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. Population Fifty-seven cases of LSIL(VaIN1) and 160 cases of HSIL(VaIN2,3). Methods Patients with VaIN were recruited and received MTLA. The detailed clinical data were recorded and the risk factors were analyzed. Main Outcome Measures The pathological cure and HPV clearance. Results The cumulative pathological cure rate was 92.0% and 96.0%, and the cumulative HPV negative rate was 77.5% and 75.5%, for the HSIL(VaIN2,3) and LSIL(VaIN1) groups respectively. Larger areas of lesions (p =0.083) and history of hysterectomy (p =0.037) were independent risk factors for pathological persistence. Menopause (p =0.006) and immunosuppression (p =0.059) were independent risk factors for HR-HPV persistent infection. Condemn use (p =0.002) was a protective factor against HR-HPV infection. It was proposed 3~5 times of laser ablation for HSIL(VaIN2,3) and 2~3 times of laser ablation for LSIL(VaIN1). Conclusions The MTLA for VaIN was effective and well-tolerated. The schematization of MTLA was decided according to the characteristics of VaIN lesions, high-risk factors and surveillance. Funding The National Natural Science Foundation of China (81974410, 81572571, 81630060, 82002769, 81230038). Keywords Laser ablation, targeting, VaIN
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