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Prognostic significance of EIF4G1 in patients with pancreatic ductal adenocarcinoma.

ABSTRACT: Background:Advances in genomics have greatly improved the survival rate in cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early, and its survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients using independent cohort data. Materials and methods:To develop a novel prognostic biomarker, we used the gene expression and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Kaplan-Meier survival curve using median values of genes as cutoff showed that EIF4G1 was the only statistically significant gene in the 3 cohorts. We analyzed the prognostic significance of EIF4G1 using the time-dependent area under the curve (AUC) of Uno's C-index, the AUC value of the receiver operating characteristics (ROC) at 3 years, and multivariate Cox analysis. We also compared EIF4G1 levels between tumors and matched non-tumor tissues. Results:EIF4G1 is the only prognostic gene in patients with PDAC, which was selected by Kaplan-Meier survival analysis. The survival curve showed that high expression of EIF4G1 was associated with poor prognosis of PDAC with a good discriminative ability in 3 independent cohorts. The risk stratifying ability of EIF4G1 was demonstrated by analyzing C-indices and AUC values. Multivariate Cox regression confirmed its prognostic significance. EIF4G1 expression was significantly higher in PDAC tissues than in the matched normal tissues. Conclusion:EIF4G1 could be used as a novel prognostic marker for PDAC and to determine suitable treatment options.

SUBMITTER: Goh TS

PROVIDER: S-EPMC6472433 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Prognostic significance of EIF4G1 in patients with pancreatic ductal adenocarcinoma.

Goh Tae Sik TS Ha Mihyang M Lee Jung Sub JS Jeong Dae Cheon DC Jung Eun Sang ES Han Myoung-Eun ME Kim Yun Hak YH Oh Sae-Ock SO

OncoTargets and therapy 20190415

<h4>Background</h4>Advances in genomics have greatly improved the survival rate in cancer patients. However, due to genetic heterogeneity, pancreatic ductal adenocarcinoma (PDAC) is still difficult to diagnose early, and its survival rate is extremely low. Therefore, we identified biomarkers that predict the prognosis of PDAC patients using independent cohort data.<h4>Materials and methods</h4>To develop a novel prognostic biomarker, we used the gene expression and clinical data from The Cancer ...[more]

PMID: 31043796

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly prevalent digestive system malignancy, with a significant impact on public health, especially in the elderly population. The advent of the Human Genome Project has opened new avenues for precision medicine, allowing researchers to explore genetic markers and molecular targets for cancer diagnosis and treatment. Despite significant advances in genomic research, early diagnosis of pancreatic cancer remains elusive due to the lack of highly sensitive and specific markers. Therefore, there is a need for in-depth research to identify more precise and reliable diagnostic markers for pancreatic cancer. In this study, we utilized a combination of public databases from different sources to meticulously screen genes associated with prognosis in pancreatic cancer. We used gene differential analysis, univariate cox regression analysis, least absolute selection and shrinkage operator (LASSO) regression, and multivariate cox regression analysis to identify genes associated with prognosis. Subsequently, we constructed a scoring system, validated its validity using survival analysis and ROC analysis, and further confirmed its reliability by nomogram and decision curve analysis (DCA). We evaluated the diagnostic value of this scoring system for pancreatic cancer prognosis and validated the function of the genes using single cell data analysis. Our analysis identifies six genes, including GABRA3, IL20RB, CDK1, GPR87, TTYH3, and KCNA2, that were strongly associated with PDAC prognosis. Clinical prognostic models based on these genes showed strong predictive power not only in the training set but also in external datasets. Functional enrichment analysis revealed significant differences between high- and low-risk groups mainly in immune-related functions. Additionally, we explored the potential of the risk score as a marker for immunotherapy response and identified key factors within the tumor microenvironment. The single-cell RNA sequencing analysis further enriched our understanding of cell clusters and six hub genes expressions. This comprehensive investigation provides valuable insights into pancreatic PDAC and its intricate immune landscape. The identified genes and their functional significance underscore the importance of continued research into improving diagnosis and treatment strategies for PDAC.

Project description:Pancreatic ductal adenocarcinoma (PDAC), as an intractable malignancy, still causes an extremely high mortality worldwide. The ubiquitin-specific protease (USP) family constitutes the major part of deubiquitinating enzymes (DUBs) which has been reported to be involved in initiation and progression of various malignancies via the function of deubiquitination. However, the biological function and clinical values of USPs in PDAC have not been comprehensively elucidated. In this study, Gene Expression Profiling Interactive Analysis (GEPIA), Gene Expression Omnibus (GEO) datasets, UALCAN database, and the Human Protein Atlas (HPA) online tool were used to analyze the expression level and the relationship between USP expression and clinicopathological features in PDAC. Survival module of HPA and Kaplan-Meier plotter (KMP) databases was recruited to explore the prognostic value of USPs. Tumor Immune Estimation Resource (TIMER) online tool and KMP databases were utilized to elucidate tumor immune infiltration and immune-related survival of USPs. CBioPortal online tool was used to identify the gene mutation level of USPs in PDAC. Both cBioPortal and LinkedOmics were used to confirm the potential biological functions of USPs in PDAC. Our study showed that USP10, USP14, USP18, USP32, USP33, and USP39 (termed as six-USPs) expressions were significantly elevated in tumor tissues. The high expression of the four USPs (USP10, USP14, USP18, and USP39) indicated a poor prognosis. A significant relationship was indicated between the expression of six-USPs and clinicopathological features. Also, the expression of six-USPs was related to promoter methylation level. Moreover, more than 40% genetic alterations and mutations were discovered in six-USPs. Furthermore, the six-USP expression was correlated with immune infiltration and immune-related prognosis. The functional analysis found that the six-USPs were involved in various biological processes and signaling pathways, such as nucleocytoplasmic transport, choline metabolism in cancer, cell cycle, ErbB signaling pathway, RIG-I-like receptor signaling pathway, TGF-β signaling pathway, and TNF signaling pathway. In conclusion, the results showed that six-USPs are potential prognostic biomarkers and can be recruited as possible therapeutic targets of PDAC.

Project description:BackgroundErythropoietin (Epo) administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC).MethodologyThe clinico-pathological relevance of hemoglobin (Hb, n = 150), serum Epo (sEpo, n = 87) and tissue expression of Epo/Epo receptor (EpoR, n = 104) was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines.ResultsCompared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05) and PDAC (p<0.001), reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46), 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99) but not in PDAC (O/P = 0.85). Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01)--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml) were not significantly different in M0 (20%) and M1 (30%) groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05). The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo.Conclusion/significanceHigher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold ≥16 mU/ml by endogenous or exogenous means may predispose to or promote metastatic progression.

Dataset Information

Prognostic significance of EIF4G1 in patients with pancreatic ductal adenocarcinoma.

Publications

Prognostic significance of EIF4G1 in patients with pancreatic ductal adenocarcinoma.

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