Dataset Information

Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: 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.

SUBMITTER: Luan H

PROVIDER: S-EPMC7479484 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma.

Luan Hong H Zhang Chuang C Zhang Tuo T He Ye Y Su Yanna Y Zhou Liping L

Disease markers 20200831

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 ...[more]

PMID: 32934754

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Project description:Immunotherapy targeting programmed cell death-1 (PD-1) has considerably improved the prognosis of patients with advanced cancers; however, its efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC) is unfavourable. To address the issue of PDAC immunotherapy, we investigated the expression of two PD-1 ligands, PD-L1 and PD-L2, in PDAC, analysed their role in survival, and explored their correlation with clinicopathological features, immune infiltration, and DNA damage response molecules. Immunohistochemistry was performed on 291 surgically resected PDAC samples. In tumour cells (TCs) and immune cells (ICs), the positivity of PD-L1 expression was 30 and 20% and that of PD-L2 expression was 40 and 20%, respectively. Moreover, PD-L1 expression on TCs correlated with its expression on ICs (p < 0.0001); a similar result was observed for PD-L2 (p < 0.0001). Nonetheless, no correlation was observed between PD-L1 and PD-L2 expression. Positive PD-L1 expression on TCs was related to N1 stage (p = 0.011) and AJCC II stage (p = 0.002), whereas positive PD-L2 expression on TCs was associated with high FOXP3+ cell infiltration (p = 0.001) and high BRCA2 expression (p < 0.0001). Survival analysis revealed that positive PD-L1 (p = 0.046) and PD-L2 (p = 0.028) expression on TCs was an independent risk factor for unfavourable disease-specific survival (DSS). Furthermore, positive PD-L2 expression on TCs was an independent risk factor for lower DSS in the pN0 (p = 0.023), moderate and well tumour differentiation (p = 0.004), low BRCA1 (p = 0.017), wild-type p53 (p = 0.034), and proficient mismatch repair (p = 0.004) subgroups. Moreover, post-operative adjuvant chemotherapy could significantly affect DSS, regardless of PD-L1/PD-L2 expression status (positive or negative) on TCs, while it only prolonged DSS in PDL1-ICs(-) (p < 0.0001) and PDL2-ICs(-) (p < 0.0001) subgroups. This study provides a comprehensive understanding of the roles of PD-L1 and PD-L2 in PDAC, supporting anti-PD-1 axis immunotherapy for PDAC.

Project description:Non-small cell lung cancer has a subtype with a high morbidity and mortality rate called lung adenocarcinoma (LUAD). It is critical to locate reliable prognostic biomarkers for LUAD at this time. Ubiquitin-conjugating enzyme E2T (UBE2T) has been found in numerous malignancies; however, its expression level and potential functions in LUAD are not completely understood at this time. A differentially expressed gene (DEG) screening method was used to identify genes that were expressed differently in 516 samples from LUAD and 59 samples from TCGA datasets. Clinicopathological markers were correlated with UBE2T expression. Using the Kaplan–Meier plotter database, UBE2T was evaluated for its prognostic value in the context of LUAD. In order to examine the importance of independent prognostic factors, both univariable and multivariable Cox regression models were applied. TIMER and CIBERSORT were utilized in order to investigate the connection that exists between UBE2T expression and tumor-infiltrating immune cells. This study collected 578 DEGs in total, as follows: 171 genes were significantly increased, while 408 genes were significantly decreased. We identified 9 survival-related DEGs in LUAD, including ASF1B, CA9, CCNB2, CCNE1, RRM2, SAPCD2, TCN1, TPX2, and UBE2T. Our attention focused on UBE2T, which was highly expressed in LUAD. A correlation was also found between high UBE2T expression and gender, age, advanced clinical stage, and decreased overall survival. In addition, multivariate analysis demonstrated UBE2T expression to be a significant independent diagnostic factor for patients suffering from LUAD. UBE2T was positively correlated with resting T cell CD4+ memory, myeloid dendritic cell resting, mast cell activated, macrophage M2, and B cell plasma, whereas it was negatively correlated with resting T cell CD4+ memory, MDC resting, MDC activated, macrophage M2, and B cell plasma. Overall, high expression levels of UBE2T correlated with poor overall survival in patients with LUAD, and UBE2T was an independent predictor involved in immune infiltration of LUAD. These findings offer fresh perspectives that contribute to our comprehension of the evolution of LUAD.

Dataset Information

Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma.

Publications

Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma.

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