Comprehensive Analysis of N6-Methyladenosine (m6A) RNA Methylation Regulators and Tumour Microenvironment Cell Infiltration Involving Prognosis and Immunotherapy in Gastroesophageal Adenocarcinomas

Duanrui Liu; Mingjie Yuan; Zongming Wang; Liping Sun; Yusong Fang; Xiaoli Ma; Lulu Zhang; Yuanxin Xing; Jingyu Zhu; Yunyun Liu; Wenshuai Zhu; Shuqin Bao; Yanfei Jia; Yunshan Wang

doi:10.1155/2022/3506518

Comprehensive Analysis of N6-Methyladenosine (m⁶A) RNA Methylation Regulators and Tumour Microenvironment Cell Infiltration Involving Prognosis and Immunotherapy in Gastroesophageal Adenocarcinomas

Can J Gastroenterol Hepatol. 2022 Nov 21:2022:3506518. doi: 10.1155/2022/3506518. eCollection 2022.

Authors

Duanrui Liu^{1

2}, Mingjie Yuan³, Zongming Wang⁴, Liping Sun⁵, Yusong Fang⁴, Xiaoli Ma², Lulu Zhang², Yuanxin Xing², Jingyu Zhu⁶, Yunyun Liu², Wenshuai Zhu², Shuqin Bao², Yanfei Jia², Yunshan Wang²

Affiliations

¹ Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
² Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan 250013, China.
³ Department of Laboratory, Jinan Central Hospital, Shandong First Medical University, Jinan 250013, China.
⁴ Department of Esophageal Surgery, Jinan Central Hospital, Shandong First Medical University, Jinan 250013, China.
⁵ Department of Infectious Diseases, Jinan Central Hospital, Shandong First Medical University, Jinan 250013, China.
⁶ Department of Gastroenterology, Jinan Central Hospital, Shandong First Medical University, Jinan 250013, China.

Abstract

Objective: Gastroesophageal adenocarcinoma (GEA) is a high deadly and heterogeneous cancer. RNA N6-methyladenosine (m⁶A) modification plays a non-negligible role in shaping individual tumour microenvironment (TME) characterizations. However, the landscape and relationship of m⁶A modification patterns and TME cell infiltration features remain unknown in GEA.

Methods: In this study, we examined the TME of GEA using assessments of the RNA-sequencing data focusing on the distinct m⁶A modification patterns from the public databases. Intrinsic patterns of m⁶A modification were evaluated for associations with clinicopathological characteristics, underlying biological pathways, tumour immune cell infiltration, oncological outcomes, and treatment responses. The expression of key m⁶A regulators and module genes was validated by qRT-PCR analysis.

Results: We identified two distinct m⁶A modification patterns of GEA (cluster 1/2 subgroup), and correlated two subgroups with TME cell-infiltrating characteristics. Cluster 2 subgroup correlates with a poorer prognosis, downregulated PD-1 expression, higher risk scores, and distinct immune cell infiltration. In addition, PPI and WGCNA network analysis were integrated to identify key module genes closely related to immune infiltration of GEA to find immunotherapy markers. COL4A1 and COL5A2 in the brown module were significantly correlated to the prognosis, PD-1/L1 and CTLA-4 expression of GEA patients. Finally, a prognostic risk score was constructed using m⁶A regulator-associated signatures that represented an independent prognosis factor for GEA. Interestingly, COL5A2 expression was linked to the response to anti-PD-1 immunotherapy, m⁶A regulator expression, and risk score.

Conclusion: Our work identified m⁶A RNA methylation regulators as an important class of players in the malignant progression of GEA and were associated with the complexity of the TME. COL5A2 may be the potential biomarker which contributes to predicting the response to anti-PD-1 immunotherapy and patients' prognosis.

MeSH terms

Adenocarcinoma* / genetics
Adenocarcinoma* / therapy
Humans
Immunologic Factors
Immunotherapy
Methylation
Prognosis
RNA / genetics
Tumor Microenvironment*

Substances

Immunologic Factors
RNA