Identification and Validation of Immune-Related Prognostic Genes in the Tumor Microenvironment of Colon Adenocarcinoma.

Shenghua Pan,Sisi Yu,Tingting Tang,Yanke Wu,Liang Zhang,Zekai Song

doi:10.3389/fgene.2021.778153

Shenghua Pan, Sisi Yu + Show 4 more

Open Access

https://doi.org/10.3389/fgene.2021.778153

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Abstract

The tumor microenvironment (TME) has been shown to be involved in angiogenesis, tumor metastasis, and immune response, thereby affecting the treatment and prognosis of patients. This study aims to identify genes that are dysregulated in the TME of patients with colon adenocarcinoma (COAD) and to evaluate their prognostic value based on RNA omics data. We obtained 512 COAD samples from the Cancer Genome Atlas (TCGA) database and 579 COAD patients from the independent dataset (GSE39582) in the Gene Expression Omnibus (GEO) database. The immune/stromal/ESTIMATE score of each patient based on their gene expression was calculated using the ESTIMATE algorithm. Kaplan–Meier survival analysis, Cox regression analysis, gene functional enrichment analysis, and protein–protein interaction (PPI) network analysis were performed. We found that immune and stromal scores were significantly correlated with COAD patients’ overall survival (log rank p < 0.05). By comparing the high immune/stromal score group with the low score group, we identified 688 intersection differentially expressed genes (DEGs) from the TCGA dataset (663 upregulated and 25 downregulated). The functional enrichment analysis of intersection DEGs showed that they were mainly enriched in the immune process, cell migration, cell motility, Toll-like receptor signaling pathway, and PI3K-Akt signaling pathway. The hub genes were revealed by PPI network analysis. Through Kaplan–Meier and Cox analysis, four TME-related genes that were significantly related to the prognosis of COAD patients were verified in GSE39582. In addition, we uncovered the relationship between the four prognostic genes and immune cells in COAD. In conclusion, based on the RNA expression profiles of 1091 COAD patients, we screened four genes that can predict prognosis from the TME, which may serve as candidate prognostic biomarkers for COAD.

Highlights

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor worldwide (Siegel et al, 2017; Siegel et al, 2020)
This study aims to identify genes that are dysregulated in the tumor microenvironment (TME) of patients with colon adenocarcinoma (COAD) and to evaluate their prognostic value based on RNA omics data
To investigate the potential correlation between the prognosis of Colon adenocarcinoma (COAD) and the immune/ stromal/ESTIMATE score, we divided patients into low-score or high-score groups by the cut-off value selected by maximally selected rank statistics in the R maxstat package

Summary

Introduction

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor worldwide (Siegel et al, 2017; Siegel et al, 2020). Colon adenocarcinoma (COAD) is the most common histological type of CRC (Barresi et al, 2015). According to GLOBOCAN 2018, CRC is the malignant tumor with the third highest incidence and the second highest mortality. The incidence of CRC among young adults is increasing (Benson et al, 2017), which brings a huge health burden to human beings worldwide. The prognosis of CRC varies in different countries around the world. Despite the continuous development of treatment methods such as operation, chemotherapy agents, and radiotherapy, the prognosis of CRC has not been significantly improved. Immunotherapy has become a promising therapeutic method for CRC patients. Current clinical trials show that only a few people can benefit from immunotherapy; finding biomarkers that can indicate treatment response and prognosis has become an urgent problem (Piawah and Venook, 2019)

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