Ning Pu1,2, Qiangda Chen1, Shanshan Gao2,3, Gao Liu4, Yayun Zhu2,4, Lingdi Yin2,5, Haijie Hu2,6, Li Wei4, Yong Wu2,7, Shimpei Maeda2,8, Wenhui Lou1, Jun Yu2, Wenchuan Wu1. 1. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 2. Department of Surgery and The Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 4. Department of Liver Surgery and Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 5. Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, and Pancreas Institute of Nanjing Medical University, Nanjing 210029, China. 6. Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China. 7. Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China. 8. Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Abstract
BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismally poor and is widely considered as an intricate genetic disorder. The mutational landscape of PDAC may directly reflect cancer immunogenicity and dictate the extent and phenotype of immune cell infiltration. In adverse, the microenvironment may also effect the gene expression of cancer cells, which is associated with clinical prognosis. Thus, it is crucial to identify genomic alterations in PDAC microenvironment and its impacts on clinical prognosis. METHODS: The gene expression profiles, mutation data and clinical information of 179 pancreatic cancer patients with an initial pathologic diagnosis ranging from 2001 to 2013 were retrieved from The Cancer Genome Atlas (TCGA) database. The MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm for calculating immune scores and stromal scores and Tumor IMmune Estimation Resource (TIMER) resource for cell infiltrations were applied in this study. RESULTS: The average immune score or stromal score of PDAC subtype was significantly higher than that of other specific subtypes. KRAS mutant cases had significantly lower immune scores (P=0.001) and stromal scores (P=0.007), in concert with lower immune scores in TP53 mutant cases (P=0.030). However, no significant difference was found in SMAD4 and CDKN2A mutations. In the cohort OS/RFS, the infiltration levels of CD8+ T cells, B cells, Macrophages, Neutrophils and DCs in high stromal score group were higher than those in the low score group (all P<0.001), as well as in immune score groups except for Macrophages in the cohort RFS. In the cohort OS/RFS, 317/379 upregulated genes and 9/6 downregulated genes were observed in the high immune score group, while 227/205 upregulated genes and 17/6 downregulated genes in the high stromal score group. With the analysis for prognostic value of DEGs, 82 and 58 DEGs respectively in the high immune and stromal score group were verified to be significantly associated with better OS (P<0.05), while 53 and 17 DEGs respectively with longer RFS (P<0.05). Functional enrichment analysis showed genes of prognostic values were significantly related to immune response. CONCLUSIONS: A list of genes with prognostic value in PDAC microenvironment were obtained from functional enrichment analysis based on immune and stromal scores, which indicates a series of potential auxiliary prognostic biomarkers for PDAC are available. Further research on these genes may be valuable and helpful to understand the crosstalk between tumor and microenvironment, new immune evasion mechanisms and underlying novel therapeutic targets in an integrated manner. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismally poor and is widely considered as an intricate genetic disorder. The mutational landscape of PDAC may directly reflect cancer immunogenicity and dictate the extent and phenotype of immune cell infiltration. In adverse, the microenvironment may also effect the gene expression of cancer cells, which is associated with clinical prognosis. Thus, it is crucial to identify genomic alterations in PDAC microenvironment and its impacts on clinical prognosis. METHODS: The gene expression profiles, mutation data and clinical information of 179 pancreatic cancer patients with an initial pathologic diagnosis ranging from 2001 to 2013 were retrieved from The Cancer Genome Atlas (TCGA) database. The MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm for calculating immune scores and stromal scores and Tumor IMmune Estimation Resource (TIMER) resource for cell infiltrations were applied in this study. RESULTS: The average immune score or stromal score of PDAC subtype was significantly higher than that of other specific subtypes. KRAS mutant cases had significantly lower immune scores (P=0.001) and stromal scores (P=0.007), in concert with lower immune scores in TP53 mutant cases (P=0.030). However, no significant difference was found in SMAD4 and CDKN2A mutations. In the cohort OS/RFS, the infiltration levels of CD8+ T cells, B cells, Macrophages, Neutrophils and DCs in high stromal score group were higher than those in the low score group (all P<0.001), as well as in immune score groups except for Macrophages in the cohort RFS. In the cohort OS/RFS, 317/379 upregulated genes and 9/6 downregulated genes were observed in the high immune score group, while 227/205 upregulated genes and 17/6 downregulated genes in the high stromal score group. With the analysis for prognostic value of DEGs, 82 and 58 DEGs respectively in the high immune and stromal score group were verified to be significantly associated with better OS (P<0.05), while 53 and 17 DEGs respectively with longer RFS (P<0.05). Functional enrichment analysis showed genes of prognostic values were significantly related to immune response. CONCLUSIONS: A list of genes with prognostic value in PDAC microenvironment were obtained from functional enrichment analysis based on immune and stromal scores, which indicates a series of potential auxiliary prognostic biomarkers for PDAC are available. Further research on these genes may be valuable and helpful to understand the crosstalk between tumor and microenvironment, new immune evasion mechanisms and underlying novel therapeutic targets in an integrated manner. 2019 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Pancreatic ductal adenocarcinoma (PDAC); The Cancer Genome Atlas (TCGA); immune score; microenvironment; prognosis; stromal score
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