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      A 6-gene risk score system constructed for predicting the clinical prognosis of pancreatic adenocarcinoma patients

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          Abstract

          Pancreatic adenocarcinoma (PAC) is the most common type of pancreatic cancer, which commonly has an unfavorable prognosis. The present study aimed to develop a novel prognostic prediction strategy for PAC patients. mRNA sequencing data of PAC (the training dataset) were extracted from The Cancer Genome Atlas database, and the validation datasets (GSE62452 and GSE79668) were acquired from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) between good and poor prognosis groups were analyzed by limma package, and then prognosis-associated genes were screened using Cox regression analysis. Subsequently, the risk score system was constructed and confirmed using Kaplan-Meier (KM) survival analysis. After the survival associated-clinical factors were screened using Cox regression analysis, they were performed with stratified analysis. Using DAVID tool, the DEGs correlated with risk scores were conducted with enrichment analysis. The results revealed that there were a total of 242 DEGs between the poor and good prognosis groups. Afterwards, a risk score system was constructed based on 6 prognosis-associated genes ( CXCL11, FSTL4, SEZ6L, SPRR1B, SSTR2 and TINAG), which was confirmed in both the training and validation datasets. Cox regression analysis showed that risk score, targeted molecular therapy, and new tumor (the new tumor event days after the initial treatment according to the TCGA database) were significantly related to clinical prognosis. Under the same clinical condition, 6 clinical factors (age, history of chronic pancreatitis, alcohol consumption, radiation therapy, targeted molecular therapy and new tumor (event days) had significant associations with clinical prognosis. Under the same risk condition, only targeted molecular therapy was significantly correlated with clinical prognosis. In conclusion, the 6-gene risk score system may be a promising strategy for predicting the outcome of PAC patients.

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          Most cited references34

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          Penalized Cox regression analysis in the high-dimensional and low-sample size settings, with applications to microarray gene expression data.

          An important application of microarray technology is to relate gene expression profiles to various clinical phenotypes of patients. Success has been demonstrated in molecular classification of cancer in which the gene expression data serve as predictors and different types of cancer serve as a categorical outcome variable. However, there has been less research in linking gene expression profiles to the censored survival data such as patients' overall survival time or time to cancer relapse. It would be desirable to have models with good prediction accuracy and parsimony property. We propose to use the L(1) penalized estimation for the Cox model to select genes that are relevant to patients' survival and to build a predictive model for future prediction. The computational difficulty associated with the estimation in the high-dimensional and low-sample size settings can be efficiently solved by using the recently developed least-angle regression (LARS) method. Our simulation studies and application to real datasets on predicting survival after chemotherapy for patients with diffuse large B-cell lymphoma demonstrate that the proposed procedure, which we call the LARS-Cox procedure, can be used for identifying important genes that are related to time to death due to cancer and for building a parsimonious model for predicting the survival of future patients. The LARS-Cox regression gives better predictive performance than the L(2) penalized regression and a few other dimension-reduction based methods. We conclude that the proposed LARS-Cox procedure can be very useful in identifying genes relevant to survival phenotypes and in building a parsimonious predictive model that can be used for classifying future patients into clinically relevant high- and low-risk groups based on the gene expression profile and survival times of previous patients.
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            Risk factors for pancreatic cancer: a summary review of meta-analytical studies.

            The aetiology of pancreatic cancer (PC) has been extensively studied and is the subject of numerous meta-analyses and pooled analyses. We have summarized results from these pooled and meta-analytical studies to estimate the fraction of PCs attributable to each of the identified risk factors.
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              A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2

              Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.
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                Author and article information

                Journal
                Oncol Rep
                Oncol. Rep
                Oncology Reports
                D.A. Spandidos
                1021-335X
                1791-2431
                March 2019
                22 January 2019
                22 January 2019
                : 41
                : 3
                : 1521-1530
                Affiliations
                [1 ]Department of Anesthesiology, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
                [2 ]Department of Vascular Surgery, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
                [3 ]Department of Orthopedics, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
                [4 ]Department of Urology, China Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
                Author notes
                Correspondence to: Dr Yan Sun, Department of Anesthesiology, China Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun, Jilin 130033, P.R. China, E-mail: smartloft@ 123456sina.com
                Article
                or-41-03-1521
                10.3892/or.2019.6979
                6365694
                30747226
                204c0bc0-ffd8-4e56-a7cb-5f78c46c8ebc
                Copyright: © Liu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 05 June 2018
                : 06 December 2018
                Categories
                Articles

                pancreatic adenocarcinoma,differentially expressed genes,risk score system,cox regression analysis,survival analysis

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