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; Bin Zheng; Ying-Xin Tan; Jia Ke; Xuan-Hui Liu; Ze-Rong Cai; Yi-Feng Zou; Ping Lan; Xiao-Jian Wu; Feng Gao

doi:10.3389/fmed.2021.686885

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

Front Med (Lausanne). 2021 Jun 15:8:686885. doi: 10.3389/fmed.2021.686885. eCollection 2021.

Authors

Yu-Feng Chen^{1

2

3}, Zhao-Liang Yu^{1

2

3}, Min-Yi Lv^{1

2

3}, Bin Zheng^{2

3}, Ying-Xin Tan⁴, Jia Ke^{1

2

3}, Xuan-Hui Liu^{1

2

3}, Ze-Rong Cai^{1

2

3}, Yi-Feng Zou^{1

2

3}, Ping Lan^{1

2

3}, Xiao-Jian Wu^{1

2

3}, Feng Gao^{1

2

3}

Affiliations

¹ Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Guangdong Institute of Gastroenterology, Guangzhou, China.
⁴ The First Hospital of Lanzhou University, Lanzhou, China.

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.

Keywords: biomarker; chemoresistance; colorectal cancer; hypoxia-related gene signature; immunosuppression.