Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma.

Zaisheng Ye,Yunqing Xie,Luchuan Chen,Miao Zheng,Zhitao Lin,Qiuhong Zheng,Yi Wang,Yi Zeng,Shenghong Wei,Chen Shu

doi:10.3389/fgene.2020.595477

Zaisheng Ye, Yunqing Xie + Show 8 more

Open Access

https://doi.org/10.3389/fgene.2020.595477

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Abstract

Cancer stem cells (CSCs), characterized by infinite proliferation and self-renewal, greatly challenge tumor therapy. Research into their plasticity, dynamic instability, and immune microenvironment interactions may help overcome this obstacle. Data on the stemness indices (mRNAsi), gene mutations, copy number variations (CNV), tumor mutation burden (TMB), and corresponding clinical characteristics were obtained from The Cancer Genome Atlas (TCGA) and UCSC Xena Browser. The infiltrating immune cells in stomach adenocarcinoma (STAD) tissues were predicted using the CIBERSORT method. Differentially expressed genes (DEGs) between the normal and tumor tissues were used to construct prognostic models with weighted gene co-expression network analysis (WGCNA) and Lasso regression. The association between cancer stemness, gene mutations, and immune responses was evaluated in STAD. A total of 6,739 DEGs were identified between the normal and tumor tissues. DEGs in the brown (containing 19 genes) and blue (containing 209 genes) co-expression modules were used to perform survival analysis based on Cox regression. A nine-gene signature prognostic model (ARHGEF38-IT1, CCDC15, CPZ, DNASE1L2, NUDT10, PASK, PLCL1, PRR5-ARHGAP8, and SYCE2) was constructed from 178 survival-related DEGs that were significantly related to overall survival, clinical characteristics, tumor microenvironment immune cells, TMB, and cancer-related pathways in STAD. Gene correlation was significant across the prognostic model, CNVs, and drug sensitivity. Our findings provide a prognostic model and highlight potential mechanisms and associated factors (immune microenvironment and mutation status) useful for targeting CSCs.

Highlights

Stomach cancer is the fifth leading cancer (7% of all cases) and the third leading cause of cancer-related death, accounting for 9% of deaths (Brenner et al, 2009)
The mRNA expression-based stemness index (mRNAsi) subgroups were clustered according to the median value of mRNAsi in stomach adenocarcinoma (STAD)
The results were consistent with the Kaplan–Meier survival curve; a significant difference in mRNAsi was observed between normal and tumor tissues in STAD (Figure 1C)

Summary

Introduction

Stomach cancer is the fifth leading cancer (7% of all cases) and the third leading cause of cancer-related death, accounting for 9% of deaths (Brenner et al, 2009). Additional epigenetic and mutational events induce CSC emergence and adenocarcinoma, including stomach adenocarcinoma (STAD) (Bessède et al, 2015) Some stemness factors such as Sox, Oct, Oct, and Nanog are related to pluripotent stem cells in STAD (Akhavan-Niaki and Samadani, 2014). The stemness of STAD was dependent on cancer-related signaling pathways, such as Notch and mTORC1 signaling, to promote gastric cancer cell proliferation. These studies demonstrated that targeting Notch and mTOR pathways in combination might be a potential therapeutic strategy for patients with STAD (Hibdon et al, 2019). The development and clinical application of adoptive immunotherapy targeting CSCs in patients with STAD may be possible in the near future (Song et al, 2018)

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