Dataset Information

Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early?stage pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and early diagnosis and assessment may enhance the quality of life and survival of patients. The prognostic value of key family 2 cystatins subunit in PDAC patients remains unknown. The potential molecular roles of family 2 cystatins and related pathways were investigated using bioinformatics analysis. The relationship of family 2 cystatin expression levels and clinical outcomes of 112 patients with early?stage PDAC were evaluated via univariate and combined survival analysis. A prognostic nomogram model was also constructed and gene set enrichment analysis was performed to investigate potential pathways in PDAC. The pathways, interaction networks, and Gene Ontology term analysis of the cystatin gene family were analyzed in the present study. Cystatin F (CST7) was identified as the key subunit of family 2 cystatins in survival analysis. PDAC patients who harbored a higher expression level of CST7 had a lower risk in overall survival (adjusted HROS=0.44, 95% CI=0.25?0.77, P=0.004) and a longer survival time in various subgroups. The prognostic nomogram indicated that the CST7 expression model effectively predicted the outcomes of patients with early?stage PDAC (predictive ability >0.75). In the gene set enrichment analysis, it was revealed that CST7 expression may be involved in immune regulation and be associated with cell adhesion. CST7 could be a useful biomarker for the prognostic prediction of early?stage PDAC after pancreaticoduodenectomy.

SUBMITTER: Yang C

PROVIDER: S-EPMC6549077 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early‑stage pancreatic ductal adenocarcinoma.

Yang Chengkun C Yu Tingdong T Liu Zhengqian Z Ye Xinping X Liao Xiwen X Wang Xiangkun X Han Chuangye C Zhu Guangzhi G Qin Wei W Peng Tao T

Oncology reports 20190424 1

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and early diagnosis and assessment may enhance the quality of life and survival of patients. The prognostic value of key family 2 cystatins subunit in PDAC patients remains unknown. The potential molecular roles of family 2 cystatins and related pathways were investigated using bioinformatics analysis. The relationship of family 2 cystatin expression levels and clinical outcomes of 112 patients with early‑stage PDAC ...[more]

PMID: 31059105

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor. The immune profile of PDAC and the immunologic milieu of its tumor microenvironment (TME) are unique; however, the mechanism of how the TME engineers the carcinogenesis of PDAC is not fully understood. This study is aimed at better understanding the relationship between the immune infiltration of the TME and gene expression and identifying potential prognostic and immunotherapeutic biomarkers for PDAC. Analysis of data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases identified differentially expressed genes (DEGs), including 159 upregulated and 53 downregulated genes. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment were performed and showed that the DEGs were mainly enriched for the PI3K-Akt signaling pathway and extracellular matrix organization. We used the cytoHubba plugin of Cytoscape to screen out the most significant ten hub genes by four different models (Degree, MCC, DMNC, and MNC). The expression and clinical relevance of these ten hub genes were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. High expression of nine of the hub genes was positively correlated with poor prognosis. Finally, the relationship between these hub genes and tumor immunity was analyzed using the Tumor Immune Estimation Resource. We found that the expression of SPARC, COL6A3, and FBN1 correlated positively with infiltration levels of six immune cells in the tumors. In addition, these three genes had a strong coexpression relationship with the immune checkpoints. In conclusion, our results suggest that nine upregulated biomarkers are related to poor prognosis in PDAC and may serve as potential prognostic biomarkers for PDAC therapy. Furthermore, SPARC, COL6A3, and FBN1 play an important role in tumor-related immune infiltration and may be ideal targets for immune therapy against PDAC.

Project description:Background: This study explored the prognostic significance of Glypican (GPC) family genes in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).Methods: A total of 112 PDAC patients from TCGA and 48 patients from GEO were included in the analysis. The relationship between overall survival and the expression of GPC family genes as well as basic clinical characteristics was analyzed using the Kaplan-Meier method with the log-rank test. Joint effects survival analysis was performed to further examine the relationship between GPC genes and prognosis. A prognosis nomogram was established based on clinical characteristics and prognosis-related genes. Prognosis-related genes were investigated by genome-wide co-expression analysis and gene set enrichment analysis (GSEA) was carried out to identify potential mechanisms of these genes affecting prognosis.Results: In TCGA database, high expression of GPC2, GPC3, and GPC5 was significantly associated with favorable survival (log-rank P?=?0.031, 0.021, and 0.028, respectively; adjusted P value?=?0.005, 0.022, and 0.020, respectively), and joint effects analysis of these genes was effective for prognosis prediction. The prognosis nomogram was applied to predict the survival probability using the total scores calculated. Genome-wide co-expression and GSEA analysis suggested that the GPC2 may affect prognosis through sequence-specific DNA binding, protein transport, cell differentiation and oncogenic signatures (KRAS, RAF, STK33, and VEGFA). GPC3 may be related to cell adhesion, angiogenesis, inflammatory response, signaling pathways like Ras, Rap1, PI3K-Akt, chemokine, GPCR, and signatures like cyclin D1, p53, PTEN. GPC5 may be involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway.Conclusion: GPC2, GPC3, and GPC5 expression may serve as prognostic indicators in PDAC, and combination of these genes showed a higher efficiency for prognosis prediction.

Project description:Adenocarcinomas of the pancreatic duct (PDAC) are characteristically aggressive tumors that are extremely challenging to treat as curative surgical resection, the definitive treatment, is seldom possible. Regretably, most patients are diagnosed with metastatic disease at the time of initial presentation. In addition, current chemotherapeutic concepts that are used for advanced disease stages show frustrating results. Thus, there is an urgent need to identify novel therapeutic molecular targets that are associated with PDAC disease. Recently, the chemokine receptor CXCR4 has been demonstrated to be highly expressed in metastatic PDAC. However, the results of the published data on CXCR4 and its association with clinicopathological variables and prognosis in PDAC seem to be heterogeneous. Consequently, to clarify the relevance of CXCR4 as a biomarker in PDAC we performed a comprehensive literature search by using PubMed and Web of Science databases to identify articles that focused on the expression of CXCR4 in PDAC by using immunohistochemistry. Subsequently, data from nine relevant studies, encompassing 1183 patients were extracted, qualitatively assessed, and entered into a meta-analysis. By using a random effects model, the pooled hazard ratio of the seven studies that reported on patients overall survival revealed a correlation between expression of CXCR4 and poor prognosis (HR 1.49; 95% CI: 1.04-2.14; P = 0.03; I2 = 74%). Although heterogeneity became evident, subgroup analyses confirmed the prognostic value of CXCR4 in PDAC, especially in high-quality studies that performed multivariate analysis. In addition, meta-analysis revealed a strong association of CXCR4 expression with the UICC stage (OR: 3.40; 95% CI: 1.67-6.92; P = 0.0007; I2 = 0%) and metastatic disease (N-status: OR: 2.55; 95% CI: 1.56-4.15; P = 0.0002; I2 = 26%; recurrence to the liver: OR: 2.80; 95% CI: 1.48-5.29; P = 0.001; I2 = 0%). Taken together, our meta-analysis suggests that CXCR4 represents a useful prognostic biomarker in PDAC and might therefore be evaluated as a potential therapeutic target in the treatment of metastatic cancer disease of the pancreas.

Dataset Information

Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early?stage pancreatic ductal adenocarcinoma.

Publications

Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early‑stage pancreatic ductal adenocarcinoma.

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