Genome-Wide Analysis Reveals Hypoxic Microenvironment Is Associated With Immunosuppression in Poor Survival of Stage II/III Colorectal Cancer Patients.

Yu-Feng Chen,Zhao-Liang Yu,Min-Yi Lv,Jia Ke,Yi-Feng Zou,Bin Zheng,Ping Lan,Ze-Rong Cai,Xiao-Jian Wu,Feng Gao,Ying-Xin Tan,Xuan-Hui Liu

doi:10.3389/fmed.2021.686885

Abstract

Background: Hypoxia is associated with a poorer clinical outcome and resistance to chemotherapy in solid tumors; identifying hypoxic-related colorectal cancer (CRC) and revealing its mechanism are important. The aim of this study was to assess hypoxia signature for predicting prognosis and analyze relevant mechanism.Methods: Patients without chemotherapy were selected for the identification of hypoxia-related genes (HRGs). A total of six independent datasets that included 1,877 CRC patients were divided into a training cohort and two validation cohorts. Functional annotation and analysis were performed to reveal relevant mechanism.Results: A 12-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohorts [TCGA, n = 509, hazard ratio (HR) = 2.14, 95% confidence interval (CI) = 1.18 – 3.89, P = 0.01; metavalidation, n = 590, HR = 2.46, 95% CI = 1.59 – 3.81, P < 0.001]. High hypoxic risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 5.1, 95% CI = 2.51 – 10.35, P < 0.001). After integration with clinical characteristics, hypoxia-related gene signature (HRGS) remained as an independent prognostic factor in multivariate analysis. Furthermore, enrichment analysis found that antitumor immune response was suppressed in the high hypoxic group.Conclusions: HRGS is a promising system for estimating disease-free survival of stage II/III CRC patients. Hypoxia tumor microenvironment may be via inhibiting immune response to promote chemoresistance in stage II/III CRC patients.

Highlights

Colorectal cancer (CRC) is the third most common cancer type in men (10.9% of all cancers) and the second in women (9.5% of all cancers) worldwide [1]
Other datasets were obtained in processed format from Gene Expression Omnibus (GEO) database through R using the Bioconductor package “GEOquery.” The batch effects were corrected using “combat” algorithm implemented in the R package “sva,” and z scores of each gene were used for the following analyses
Among 3,444 hypoxiarelated genes (HRGs) selected from Molecular Signatures Database (MSigDB), 3,184 HRGs were detected in the meta-analysis in this study

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer type in men (10.9% of all cancers) and the second in women (9.5% of all cancers) worldwide [1]. Hypoxia is associated with a poorer clinical outcome and resistance to chemotherapy in solid tumors; identifying hypoxic-related colorectal cancer (CRC) and revealing its mechanism are important. Results: A 12-gene signature was derived, which was prognostic for stage II/III CRC patients in two validation cohorts [TCGA, n = 509, hazard ratio (HR) = 2.14, 95% confidence interval (CI) = 1.18 – 3.89, P = 0.01; metavalidation, n = 590, HR = 2.46, 95% CI = 1.59 – 3.81, P < 0.001]. High hypoxic risk was correlated with worse prognosis in CRC patients without adjuvant chemotherapy (HR = 5.1, 95% CI = 2.51 – 10.35, P < 0.001). After integration with clinical characteristics, hypoxia-related gene signature (HRGS) remained as an independent prognostic factor in multivariate analysis. Hypoxia tumor microenvironment may be via inhibiting immune response to promote chemoresistance in stage II/III CRC patients

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