Genetic landscape of prognostic value in pancreatic ductal adenocarcinoma microenvironment

Ning Pu, Qiangda Chen, Shanshan Gao, Gao Liu, Yayun Zhu, Lingdi Yin, Haijie Hu, Li Wei, Yong Wu, Shimpei Maeda, Wenhui Lou, Jun Yu, Wenchuan Wu


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.