Prognostic Value In Cervical Cancer Research Articles

Qualitative and quantitative changes in mitochondrial DNA associated with cervical cancer: A comprehensive review.

Cervical cancer is the fourth most commonly diagnosed cancer in women and is considered a preventable disease, as vaccination and screening programs effectively reduce its incidence and mortality rates. Disease physiopathology and malignant cell transformation is a complex process, but it is widely known that high-risk HPV (hrHPV) infection is a necessary risk factor for cancer development. Mitochondria, cell organelles with important bioenergetic and biosynthetic functions, are important for cell energy production, cell growth, and apoptosis. Mitochondrial DNA is a structure that is particularly susceptible to quantitative (mtDNA copy number variation) and qualitative (sequence variations) alterations that are associated with various types of cancer. Novel biomarkers with diagnostic and prognostic value in cervical cancer can be evaluated to provide higher specificity and complement hrHPV molecular testing, which is the most recommended method for primary screening. In accordance with this, this review aimed to assess mitochondrial alterations associated with cervical cancer in clinical cervicovaginal samples, in order to unravel their possible role as specific diagnostic and prognostic biomarkers for cervical malignancy, and also to guide the understanding of their involvement in carcinogenesis, HPV infection, and disease progression.

FBXO5 acts as a novel prognostic biomarker for patients with cervical cancer.

Background: Cervical cancer (CC) remains one of the most common and deadly malignancies in women worldwide. FBXO5, a protein-coding gene, is highly expressed in a variety of primary tumors and promotes tumor progression, however, its role and prognostic value in CC remain largely unknown. Methods: A key differential gene, FBXO5, was screened according to WGCNA based on immunohistochemical assays of clinical samples, multiple analyses of the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including survival analysis, tumor mutational burden, GO, KEGG, tumor immune infiltration, and chemotherapeutic drug sensitivity, to explore the expression and prognostic value of FBXO5 in CC. The migration and invasiveness of cervical cancer cells following FBXO5 knockdown and overexpression were examined using wound healing and transwell assays, and the viability of cancer cells was assessed using CCK8 and EdU assays. Results: FBXO5 was discovered to be substantially expressed in CC tissues using data from our CC cohort and the TCGA database, and a survival analysis indicated FBXO5 as a predictive factor for poor overall survival in CC patients. In vitro, CC cells were more inclined to proliferate, migrate, and invade when FBXO5 was upregulated as opposed to when it was knocked down.

Tertiary lymphoid structure prevalence and prognostic value in cervical cancer.

e17521 Background: Recurrent or progressive cervical cancer have limited second-line treatment options. Response rates are often poor to second-line therapy (average response rate of 15%). Identification of factors which predict response to immunotherapy and targets to enhance the immune response are critically needed in cervical cancer. Chronic inflammation can initiate an immune response in non-secondary lymphoid organs (SLO) and form a Tertiary Lymphoid Structure (TLS). TLS is composed of immune cells clustered and organized and responsible for immune cell chemotaxis, which impacts cancer therapeutic response. Chemokine ligand 13 (CXCL13) is related to B cell attraction and TLS formation. Recent work from our group demonstrated human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) exhibited greater tumor infiltrating B cells (TIL-Bs) and TLS vs HPV negative disease indicating a role for viral infection in immune infiltration. Most cervical cancer is caused by HPV infection, therefore we investigated prognostic significance of immune infiltration in cervix cancer. Methods: A cohort analysis was conducted on 43 patients diagnosed with early stage cervical cancer. The presence of B cells, CD8 T cells, and CXCL13 was analyzed using singleplex immunohistochemistry staining. We separated infiltration into high infiltration and low infiltration, defined by their median value. TLS was identified using a multiplex immunofluorescence for TLS maturity panel. Histological findings were associated with cohort data. Results: High intratumoral infiltration of CD8 T cells was associated with longer overall survival in cancer patients. Median survival was 45 months for low infiltration group, whereas it was not reached by higher T cell infiltration (p < 0.05). The prognostic value of T cell infiltration was stronger in adenocarcinoma, typically associated with worse outcomes, than in squamous cell carcinoma. In adenocarcinoma, median survival was 58 months for low T cell infiltration, it was not reached by high infiltration group. CXCL13 levels were prognostic for recurrence-free survival, with median survival of 53 months in low expression group and not reached in high CXCL13 presence group (p < 0.05). The presence of TLS compared to low B cell infiltration was associated to higher survival, with 0% of deaths in the TLS group vs 40% in low B cell infiltration. While there was no correlation between TIL-B and patient outcomes, the presence of B cells in the aggregation process and higher CXCL13 levels were associated with improved survival, with 9% deaths vs 36% in low B cell group, possibly due to the support of TLS formation by B cell aggregation surrounded by CXCL13. Conclusions: Our study suggests that the presence of TLS, whether forming or established, is linked to improved clinical outcomes in cervical cancer. Further research is necessary to investigate the response of this cancer type to immunotherapy.

Utility of pre-treatment 18 F-fluorodeoxyglucose PET radiomic analysis in assessing nodal involvement in cervical cancer.

Intratumor heterogeneity has prognostic value in cervical cancer, which can be depicted on 18 F-fluorodeoxyglucose ( 18 F-FDG) PET/computed tomography (PET/CT) and then quantitatively characterized by texture features. This study aimed to evaluate the discriminative performance and predictive ability of the texture features in determining lymph node involvement in cervical cancer. A total of 101 patients with newly diagnosed cervical cancer, who underwent pre-treatment whole-body 18 F-FDG PET/CT imaging were retrospectively recruited. Patients were categorized based on their nodal status. Thirty-five radiomic features together with the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the primary cervical tumors were extracted. Conventional indices were used to build logistic regression model and texture features were used to build random forest model. The performances for differentiating nodal status were assessed by receiver operating characteristic analysis. Conventional PET indices were significantly higher in patients with nodal involvement compared to those without: SUVmax = 14.22 vs. 10.05; MTV = 57.02 vs. 28.73; TLG = 492.8 vs. 188.8 ( P  < 0.05). Nineteen radiomic features describing regional heterogeneity were significantly different between nodal involvements. Area under the curves of the models with conventional indices and PET texture features for discriminating nodal status were 0.72 and 0.76, respectively. PET-derived radiomic features had moderate performance in discriminating nodal involvement in cervical cancer; and they did not outperform model based on conventional indices.

CD40/CD40L expression and its prognostic value in cervical cancer

CD40/CD40L expression and its prognostic value in cervical cancer

An integrated analysis of single-cell and bulk transcriptomics reveals EFNA1 as a novel prognostic biomarker for cervical cancer.

Cervical cancer is a serious threat to women's health and lives worldwide. The recovery and survival of cervical cancer can be improved by customizing therapy strategies based on individual-specific gene expression patterns. EFNA1 was reported to be dysregulated in many cancers and associated with their overall survivals, but its prognostic value in cervical cancer is still unclear. In this study, we performed analyses on the single-cell and bulk RNA sequencing data to study the role of EFNA1 in cervical cancer. EFNA1 was found to be significantly upregulated in cervical cancer tissue, especially the cancer cell subgroup within tumors, which was verified by immunohistochemistry. Through Cox regressions, we found that high EFNA1 expression is an independent risk factor for cervical cancer. Nomogram analysis indicated that EFNA1 could be a predicting factor for the survival probabilities of cervical cancer. Gene ontology and pathway analyses showed that EFNA1 was involved in many tumorigenesis pathways, protein, and virus productions. These findings suggested that EFNA1 could be a prognostic biomarker and potential therapeutic target for cervical cancer.

The co-expression of CBX8 and PD-L1 and prognostic value in cervical cancer.

Chromobox homolog 8 (CBX8) plays an important role in the occurrence and development of various tumors, and is closely related to the prognosis of patients with cancer. However, the occurrence, development, and prognostic value of CBX8 in cervical cancer have not been reported yet.In this study, immunohistochemistry was used to detect the expression of CBX8 in cervical cancer tissues and the corresponding normal tissues adjacent to the tumor. Furthermore, the relationship between CBX8 and programmed death-ligand 1 (PD-L1) expression, clinicopathological characteristics, and prognosis of cervical cancer were explored, and the prognostic value of CBX8 in cervical cancer was clarified.In this study, the results of immunohistochemistry using tissue chips obtained from patients with cervical cancer showed that CBX8 was highly expressed in cervical cancer tissues, and its expression was proportional to the international federation of gynecology and obstetrics (FIGO) stage. Disease-free and overall survival of patients with high CBX8 expression in cervical cancer were significantly shorter than those of patients with low CBX8 expression. Thus, CBX8 was found to be an independent prognostic factor for patients with cervical cancer. In addition, CBX8 and PD-L1 co-expression model could better predict the prognosis of patients with cervical cancer, and its area under the receiver operating characteristic curve was similar to that of FIGO stage.CBX8 may be an independent prognostic factor for cervical cancer. Moreover, the CBX8 and PD-L1 co-expression model could predict the postoperative survival of patients with cervical cancer objectively and reliably, which will aid clinicians to shunt patients with cervical cancer based on the risk of death, develop a reasonable treatment plan, and provide personalized prognosis.

Prognostic Role of Matrix Metalloproteinases in Cervical Cancer: A Meta-Analysis.

ObjectiveStudies have published the association between the expression of matrix metalloproteinases (MMPs) and the outcome of cervical cancer. However, the prognostic value in cervical cancer remains controversial. This meta-analysis was conducted to evaluate the prognostic functions of MMP expression in cervical cancer.MethodsA comprehensive search of PubMed, Embase, and Web of Science databases was conducted to identify the eligible studies according to defined selection and excluding criteria and analyzed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Fixed and random effects models were evaluated through the hazard ratios (HRs) and 95% confidence intervals (CIs) to estimate the overall survival (OS), recurrence-free survival (RFS), and progress-free survival (PFS).ResultsA total of 18 eligible studies including 1967 patients were analyzed for prognostic value. Totally 16 selected studies including 21 tests were relevant to the cervical cancer OS, 4 studies focused on RFS, and 1 study on PFS. The combined pooled HRs and 95% CIs of OS were calculated with random-effects models (HR = 1.64, 95% CI = 1.01–2.65, P = .000). In the subgroup analysis for OS, there was no heterogeneity in MMP-2 (I2 = .0%, P = .880), MMP-1 (I2 = .0%, P = .587), and MMP-14 (I2 = 28.3%, P = .248). In MMP-7 and MMP-9, the heterogeneities were obvious (I2 = 99.2% (P = .000) and I2 = 77.9% (P = .000), respectively). The pooled HRs and 95% CIs of RFS were calculated with fixed-effects models (HR = 2.22, 95% CI = 1.38–3.58, P = .001) and PFS (HR = 2.29, 95% CI = 1.14–4.58, P = .035).ConclusionsThe results indicated that MMP overexpression was associated with shorter OS and RFS in cervical cancer patients. It suggested that MMP overexpression might be a poor prognostic marker in cervical cancer. Research Registry Registration Number: reviewregistry 1159.

GJA1 Expression and Its Prognostic Value in Cervical Cancer.

Gap Junction Protein Alpha 1 (GJA1) belongs to the gap junction family and has been widely studied in cancers. We evaluated the role of GJA1 in cervical cancer (CC) using public data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. The difference of GJA1 expression level between CC and normal tissues was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA), six GEO datasets, and the Human Protein Atlas (HPA). The relationship between clinicopathological features and GJA1 expression was analyzed by the chi-squared test and the logistic regression. Kaplan–Meier survival analysis and Cox proportional hazard regression analysis were used to assessing the effect of GJA1 expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways regulated by GJA1. Immune Cell Abundance Identifier (ImmuCellAI) was chosen to analyze the immune cells affected by GJA1. The expression of GJA1 in CC was significantly lower than that in normal tissues based on the GEPIA, GEO datasets, and HPA. Both the chi-squared test and the logistic regression showed that high-GJA1 expression was significantly correlated with keratinization, hormone use, tumor size, and FIGO stage. The Kaplan–Meier curves suggested that high-GJA1 expression could indicate poor prognosis (p = 0.0058). Multivariate analysis showed that high-GJA1 expression was an independent predictor of poor overall survival (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013). GSEA showed many cancer-related pathways, such as the p53 signaling pathway and the Wnt signaling pathway, were enriched in the high-GJA1-expression group. Immune cell abundance analysis revealed that the abundance of CD8 naive, DC, and neutrophil was significantly increased in the high-GJA1-expression group. In conclusion, GJA1 can be regarded as a potential prognostic marker of poor survival and therapeutic target in CC. Moreover, many cancer-related pathways may be the critical pathways regulated by GJA1. Furthermore, GJA1 can affect the abundance of immune cells.

A microRNA-Messenger RNA Regulatory Network and Its Prognostic Value in Cervical Cancer.

Cervical cancer (CC) is the fourth commonest cancer in women worldwide. Increasing evidence proves that microRNA (miRNA)-messenger RNA (mRNA) network is involved in CC. In this study, miRNA and mRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Differently expressed miRNAs (DE-miRNAs) and mRNAs (DE-mRNAs) were obtained by "Empirical Analysis of Digital Gene Expression Data in R (EdgeR)" package. Then, functional analyses were conducted. With Cytoscape software, a protein-protein interaction (PPI) network was established to identify hub genes that were used for building an miRNA-hub gene network. Next, a prognostic signature based on hub genes was constructed by Cox regression analysis, and its prognostic value was assessed by a nomogram. Finally, the relationship between immune cell infiltration and the three genes in the prognostic model was investigated by using the CIBERSORT algorithm. We screened out 5096 DE-mRNAs and 114 DE-miRNAs between healthy cervical and CC tissues. Then, 102 target DE-mRNAs of upregulated DE-miRNAs and 150 target DE-mRNAs of downregulated DE-miRNAs were obtained. PPI network demonstrated 20 hub nodes with higher connectivity. DE-mRNAs were mostly enriched in pathways in cancer, cell cycle, and proteoglycans in cancer. The miRNA-hub gene network showed that most hub genes could be potentially modulated by miR-200c-3p, miR-23b-3p, and miR-106b-5p. Quantitative real-time PCR proved that 10 miRNAs were downregulated and 6 mRNAs were upregulated markedly in CC tissues. Furthermore, a prognostic signature was established based on enhancer of zeste homolog 2 (EZH2), Fms-related tyrosine kinase 1 (FLT1), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The area under the curve value of the 5-year receiver operating characteristic curve was 0.609. The three genes were also found to be related to the infiltration of six types of immune cells, including dendritic cells, macrophages M0 and M1, mast cells, and monocytes. In conclusion, the development of CC is regulated by the miRNA-mRNA network we proposed in this study.

Differential effect of GLUT1 overexpression on survival and tumor immune microenvironment of human papilloma virus type 16-positive and -negative cervical cancer

Glucose transporter-1 (GLUT1) has been proposed as a prognosticator in various cancers associated with therapeutic resistance and immune evasion; however little data is available on the role of GLUT1 in cervical cancer. Most cervical cancers are caused by human papilloma virus (HPV), but studies on the treatment response and prognosis depending on the HPV subtype, are conflicting. This hypothesis-generating study aims to investigate the prognostic impact of GLUT1 in cervical cancer, in conjunction with HPV subtype. Clinicopathologic factors, along with mRNA expression data were obtained using The Cancer Genome Atlas database. Tumor HPV status and immune cell scores were extracted from previous publications. In total, 298 patients were analyzed. High GLUT1 expression was associated with old age, squamous cell carcinoma, high tumor stage, pelvic lymph node metastases, and low hysterectomy rate. Multivariate survival analysis revealed that high GLUT1 expression (Hazard ratio (HR) 2.57, p = 0.002) and HPV16 subtype (HR 0.56, p = 0.033) were independent prognostic factors for overall survival. In the subgroup analysis, poor prognostic impact of high GLUT1 expression was maintained in HPV16-positive group (p < 0.001), but not in HPV16-negative group (p = 0.495). Decreased immune cell scores of CD8+ T cells, B cells, and Th1 cells by high GLUT1 expression were observed only in HPV16-positive group. In conclusion, these results suggested that GLUT1 expression and HPV16 subtype might have an independent prognostic value in cervical cancer. GLUT1-mediated immunomodulation might be an important cause of treatment failure, especially in HPV16-positive group.

Prognostic implications of genotyping and p16 immunostaining in HPV-positive tumors of the uterine cervix.

Human papillomaviruses (HPVs) are the causative agents of carcinoma of the uterine cervix. A number of HPV genotypes have been associated with cervical cancer and almost all tumors associated with HPV show strong p16 expression. However, there is little information on the possible impact of the HPV genotype and p16 immunostaining on the clinicopathological features or their prognostic value in cervical carcinoma. We evaluated a series of 194 patients with HPV-positive cervical cancers treated at our institution, focusing on the clinicopathological features and the relationship of the HPV genotypes and p16 immunostaining with the prognosis. A single HPV type was identified in 149 (77%) tumors, multiple HPV infection was detected in 30 cases (15%), and undetermined HPV type/s were identified in 15 (8%) carcinomas. HPV 16 and/or 18 were detected in 156 (80%) tumors. p16 was positive in 186 (96%) carcinomas, but eight tumors (4%) were negative for p16 (seven squamous cell carcinomas, one adenocarcinoma); 5/8 caused by HPV 16 and/or 18. Patients with HPV 16 and/or 18 were younger (49 ± 15 vs. 57 ± 17 years, p < 0.01) and more frequently had nonsquamous tumors than patients with other HPV types (24% [37/156] vs. 0% [0/38]; p = 0.01). Neither the HPV type nor multiple infection showed any prognostic impact. Patients with p16-negative tumors showed a significantly worse overall survival than women with p16-positive carcinomas (45 vs. 156 months, p = 0.03), although no significant differences in disease-free survival were observed. In the multivariate analysis, negative p16 immunostaining was associated with a worse overall survival together with advanced FIGO stage and lymph node metastases. In conclusion, the HPV genotype has limited clinical utility and does not seem to have prognostic value in cervical cancer. In contrast, a negative p16 result in patients with HPV-positive tumors is a prognostic marker associated with a poor overall survival.

Differential Effect of GLUT1 Overexpression on Survival and Tumor Immune Microenvironment of Human Papilloma Virus Type 16-Positive and -Negative Cervical Cancer

Glucose transporter-1 (GLUT1) has been reported as a poor prognosticator associated with radioresistance and immune evasion through metabolic communication in various cancers, but little data is available on cervical cancer. Meanwhile, most cervical cancer is known to be caused by human papilloma virus (HPV), but treatment response and prognosis according to the HPV subtype are also unknown. This hypothesis-generating study was conducted to investigate the prognostic impact of GLUT1 in cervical cancer, in conjunction with HPV subtype. Clinicopathologic factors along with mRNA expression data were obtained using The Cancer Genome Atlas database. Tumor HPV status and immune cell abundance scores were extracted from previous publications. Total 298 patients with appropriate information were analyzed. High GLUT1 expression was associated with old age, squamous cell carcinoma, high tumor stage, pelvic lymph node metastases, and low hysterectomy rate. HPV16 positivity itself was not associated with other factors, except low tumor grade. Multivariate survival analysis revealed that high GLUT1 expression (HR 2.57, p = 0.002) and HPV16 subtype (HR 0.56, p = 0.033) were independent prognostic factors for OS. In the subgroup analysis, poor prognostic impact of high GLUT1 expression was maintained in the HPV16-positive group (p < 0.001), but not in the HPV16-negative group (p = 0.495). Decreased immune cell abundance scores of B cells, CD8 T cells, and Th1 cells by high GLUT1 expression were observed only in the HPV16-positive group. Despite of heterogenous treatments, our results suggested that GLUT1 expression and HPV16 subtype may have an independent prognostic value in cervical cancer. Especially in the HPV16-positive group, GLUT1-mediated immunomodulation might be an important cause of treatment failure. Further proof-of-concept study is warranted to identify novel immunometabolic targets to overcome radioresistance.

Hypomethylation of the lncRNA SOX21-AS1 has clinical prognostic value in cervical cancer

AimsCervical cancer seriously affects women's health. The function of methylated alterations in the long non-coding RNAs (lncRNAs) promote the progression and metastasis of cancer. Our study aims to identify the functional effects of lncRNA methylation in cervical carcinogenesis. Main methodsGenome-wide DNA methylation of 6 samples was assessed using the Illumina Infinium MethylationEPIC BeadChip. RNA sequencing (RNA-seq) data and survival follow-up time of 307 samples from The Cancer Genome Atlas (TCGA) dataset were enrolled in this study. The statistical analysis and graphical work were mainly realized by R language. Key findingsMethylation map identified 3962 hypermethylated CpG sites and 4484 hypomethylated CpG sites in cervical cancer (|Δβ| ≥ 0.20). Bioinformatic analysis of the lncRNA expression identified 363 upregulated and 664 downregulated lncRNAs with log2 (fold change) ≥ 1.00 in squamous cervical carcinoma (SCC) samples. Weighted gene co-expression network analysis (WGCNA) and Venn diagram revealed that lncRNA MAGI2 antisense RNA 3 (lncRNA MAGI2-AS3), lncRNA WT1 antisense RNA (lncRNA WT1-AS) and lncRNA SOX21 antisense divergent transcript 1 (lncRNA SOX21-AS1) were important methylation changed lncRNAs. Kaplan-Meier survival curves showed only lncRNA SOX21-AS1 had clinical prognostic value in cervical cancer. Gene set enrichment analysis (GSEA) suggest that lncRNA SOX21-AS1 involve in the multiple cellular processes and might significantly suppress cervical tumorigenesis. SignificanceThese insights into the functional role of lncRNA SOX21-AS1 DNA methylome alterations in cervical cancer might promote clinically new applicable in diagnosis and prognosis.

High methylation of ZNF582 in cervical adenocarcinoma affects radiosensitivity and prognosis.

Our previous study demonstrated hypermethylation of the ZNF582 gene in cervical cancer, but its prognostic value in cervical cancer, especially in cervical adenocarcinoma (CAC), remains unclear. The present study aimed to investigate the value of ZNF582 gene methylation for diagnosis and prediction of radiochemotherapy sensitivity and prognosis in CAC. We first determined ZNF582 methylation levels using quantitative methylation-specific PCR in a training set. Disease-free survival and overall survival (DFS and OS) rates were estimated using the Kaplan-Meier method. A Cox regression model was used to assess the prognostic significance of ZNF582 gene methylation in CAC patients. Immunohistochemistry was used to test ZNF582 protein expression in CAC tissues, and an MTT assay evaluated the sensitivity of Hela cells (with or without ZNF582 transfection) to radiation and chemotherapy. The ZNF582 gene showed a higher level of methylation in the CAC group than in the noncancer group, and patients negative for ZNF582 methylation had worse prognoses. We also found that ZNF582 methylation levels were reduced in concomitant chemo-radio-therapy (NCRT) patients compared with that in non-NCRT patients. Methylation-negative status was correlated with high ZNF582 protein expression, and ZNF582 protein overexpression could increase resistance to radiation and chemotherapy in Hela cells. Aberrant high methylation of ZNF582 may be a potential biomarker for CAC detection and prognosis monitoring. Overexpression of ZNF582 protein could increase CAC chemoradiotherapy resistance.

Genomic Network-Based Analysis Reveals Pancreatic Adenocarcinoma Up-Regulating Factor-Related Prognostic Markers in Cervical Carcinoma.

We previously showed that PAUF is involved in tumor development and metastases in cervical cancer. This study was conducted to discover novel molecular markers linked with PAUF in cervical cancer using genomic network analysis and to assess their prognostic value in cervical cancer. Three PAUF-related genes were identified using in-silico network-based analysis of the open genome datasets. To assess the expression of these genes and their relationship to the outcome of cervical cancer, immunohistochemical analysis was performed using cervical cancer TMA. The associations of the identified proteins with clinicopathologic characteristics and prognosis were examined. AGR2, BRD7, and POM121 were identified as interconnected with PAUF through in-silico network-based analysis. AGR2 (r = 0.213, p < 0.001) and POM121 (r = 0.135, p = 0.013) protein expression were positively correlated with PAUF. BRD7High and AGR2Low were significantly associated with favorable disease-free survival (DFS) (p = 0.009 and p < 0.001, respectively), and in combination with PAUFHigh, even more significantly favorable DFS observed (p < 0.001 for both). In multivariate analysis, AGR2High (HR = 3.16, p = 0.01) and BRD7High (HR = 0.5, p = 0.025) showed independent prognostic value for DFS. In a random survival forest (RSF) model, the combined clinical and molecular variable model predicted DFS with significantly improved power compared with that of the clinical variable model (C-index of 0.79 vs. 0.75, p < 0.001). In conclusion, AGR2 and BRD7 expression have prognostic significance in cervical cancer and provide opportunities for improved treatment options. Genomic network-based approaches using the cBioPortal may facilitate the discovery of additional biomarkers for the prognosis of cervical cancer and may provide new insights into the biology of cervical carcinogenesis.

Expression of fibroblast growth factor receptor family members is associated with prognosis in early stage cervical cancer patients.

BackgroundThe oncogenic role of the fibroblast growth factor receptor (FGFR) has been recognized in a number of different cancer types. However, the prognostic significance of FGFRs has not been elucidated yet in cervical cancer. In the present study, we investigate the expression of FGFRs and their prognostic value in cervical cancer patients.MethodsFGFR1, FGFR2, FGFR3, and FGFR4 expression was determined by immunohistochemistry in conjunction with quantitative digital image analysis of 336 formalin-fixed, paraffin-embedded cervical cancer tissues and 61 normal cervical tissues, as well as NCI60 cell microarray. Subsequently, the association between clinicopathological characteristics and patient survival was assessed.ResultsFGFRs proteins were differentially expressed in the NCI60 cell line panel and showed considerable correlation between protein and mRNA expression. The expression of FGFR1, FGFR2, and FGFR4 were higher in cancer tissues than in normal tissues, whereas the expression of FGFR3 was higher in normal tissues. FGFR1 was highly expressed in adeno-/adenosquamous carcinoma (P = 0.020), while FGFR2, FGFR3, and FGFR4 expression were more prominent in squamous cell carcinoma (P < 0.001, P < 0.001, and P = 0.020, respectively). FGFR2 expression was significantly higher in small sized tumors (P = 0.020). Additionally, high FGFR2 and FGFR4 were correlated with negative lymph node metastasis (P = 0.048 and P = 0.040, respectively). FGFR1, FGFR2, and FGFR3 were highly expressed in tumors without parametrial involvement (P = 0.030, P = 0.005, and P = 0.010, respectively). In survival analysis, high expressions of FGFR2, FGFR3, and FGFR4 was associated with longer disease-free survival (P = 0.006, P = 0.035, P = 0.001, respectively) and overall survival (P = 0.003, P = 0.002, P = 0.003, respectively). Notably, the co-expression of all three FGFRs was significantly associated with favorable disease-free survival (P < 0.001) and overall survival (P < 0.001), compared to the negative expressions of the three FGFRs. The prognostic significance persisted in the cox regression analysis.ConclusionsThe frequent expression of members of the FGFR family in cervical cancer suggests they may have prognostic and therapeutic relevance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0874-0) contains supplementary material, which is available to authorized users.

Expression and Effects of High-Mobility Group Box 1 in Cervical Cancer

We investigated the significance of high- mobility group box1 (HMGB1) and T-cell-mediated immunity and prognostic value in cervical cancer. HMGB1, forkhead/winged helix transcription factor p3 (Foxp3), IL-2, and IL-10 protein expression was analyzed in 100 cervical tissue samples including cervical cancer, cervical intraepithelial neoplasia (CIN), and healthy control samples using immunohistochemistry. Serum squamous cell carcinoma antigen (SCC-Ag) was immunoradiometrically measured in 32 serum samples from 37 cases of squamous cervical cancer. HMGB1 and SCC-Ag were then correlated to clinicopathological characteristics. HMGB1 expression tends to increase as cervical cancer progresses and it was found to be significantly correlated to FIGO stage and lymph node metastasis. These findings suggest that HMGB1 may be a useful prognostic indicator of cervical carcinoma. In addition, there were significant positive relationships between HMGB1 and FOXP3 or IL-10 expression (both p < 0.05). In contrast, HMGB1 and IL-2 expression was negatively correlated (p < 0.05). HMGB1 expression may activate Tregs or facilitate Th2 polarization to promote immune evasion of cervical cancer. Elevated HMGB1 protein in cervical carcinoma samples was associated with a high recurrence of HPV infection in univariate analysis (p < 0.05). HMGB1 expression and levels of SCC-Ag were directly correlated in SCC (p < 0.05). Thus, HMGB1 may be a useful biomarker for patient prognosis and cervical cancer prediction and treatment.

826 RAD51 G172T Polymorphism – a Prognostic Value in Cervical Cancer?

826 RAD51 G172T Polymorphism – a Prognostic Value in Cervical Cancer?

The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of China

BackgroundStudies have shown that type-specific persistence of high-risk human papillomavirus (HPV) infection contributed significantly to cervical carcinogenesis.MethodsIn this population-based study (on 24041 women), we report on the prevalent genotypes of HPVs and the prevalent genotypes of HPV persistent infection in the northeast of China.ResultsOur results showed that in HPV infected women (45.6% in total), (95% CI, 44.97%–46.23%), 17.35% (95%CI, 16.87%–17.83%) suffered persistent infection. The most common high-risk HPV types in persistent positivity were HPV-16 (18.21%; 95%CI, 17.04%–19.38%), HPV-58 (13.2%; 95%CI, 12.17%–14.23%), HPV-18 (8.66%; 95%CI, 7.81%–9.51%), HPV-52 (7.06%; 95% CI, 6.28%–7.84%) and HPV-33 (6.78%; 95% CI, 6.02%–7.54%). The prevalence of persistent infections with HPV-16,–58, −18, −52 and 33 in cervicitis were lower compared to those in CIN (all P < 0.05). HPV-58, −33 and multiple HPV persistent positivity were significantly associated with older age (all P < 0.05). HPV-18 persistent positivity was significantly associated with adenocarcinoma and lymphatic metastasis (all P < 0.05). HPV-18 persistent positivity was associated with cervical cancer prognosis (P <0.0001). Multivariate analyses showed that HPV-18 persistent positivity, (RR = 1.704, 95%CI = 1.095–2.654, p = 0.028) and lymphatic metastasis (RR = 2.304, 95%CI = 1.354–3.254, P = 0.015) were independent predictors for 3-year survival in cervical cancer.Conclusionswe provided extensive results of HPV genotype prevalence and distribution in the northeast of China. HPV genotyping is worthwhile to perform because of its independent prognostic value in cervical cancer