综合分析m6A RNA甲基化调节因子与肺癌免疫浸润及预后的相关性

Comprehensive Analysis of Immune Infiltrates and Prognosis of m6A RNA Methylation Regulators in Lung Cancer

关键词:  N6甲基化腺苷  肺鳞癌  肺腺癌  免疫浸润  免疫微环境

Key words:  N6-methyl-adenosine(m6A)  lung squamous carcinoma  lung adenocarcinoma  immune infiltration  immune microenvironment

摘要:

目的 初步探究N6甲基化腺苷（N6-methyl-adenosine，m6A）甲基化调节因子在肺癌肿瘤免疫微环境中的潜在作用及机制。方法 基于TCGA数据库，本研究利用生物信息学综合分析m6A RNA甲基化调节因子与肺癌免疫浸润及预后的相关性。结果 多个m6A RNA甲基化调节因子在肺鳞癌和肺腺癌中差异性表达。然而，ALKBH5仅在肺鳞癌中显著高表达，METTL3和YTHDF3仅在肺腺癌中显著高表达，HNRNPA2B1与肺鳞癌YTHDC1、肺腺癌RBM15表达相关。通过对18个m6A甲基化调节因子的一致性聚类，发现肺鳞癌不同亚型的总生存率无统计学差异。在肺腺癌中，PD-1、PD-L1表达在癌及癌旁组织中无显著差异，且与m6A甲基化调节因子无明显相关性。聚类分析后发现m6A甲基化调节因子在肺腺癌肿瘤免疫微环境中起重要作用，其中Cluster 2组PD-L1表达下降、免疫细胞浸润较高，但是生存期较Cluster 1组延长。Cluster 2组与树突细胞静息、肥大细胞静息、γδ T细胞浸润更相关。Cluster 1组生存期短可能与G2M检查点、E2F通路、MYC通路、MTORC1通路、Wnt/beta-catenin通路，以及树突状细胞激活、巨噬细胞M1、滤泡T辅助细胞浸润水平较高有关。单因素Cox分析结果表明4个甲基化结合蛋白与预后相关，其中IGF2BP3、HNRNPA2B1和IGF2BP2为危险因子，YTHDF2为保护因子。结论 m6A RNA甲基化调节因子与肺腺癌免疫浸润及预后有密切相关性。

Abstract:

OBJECTIVE To preliminarily explore the potential role and mechanism of N6-methyl-adenosine(m6A) methylation regulators in the immune microenvironment of lung cancer. METHODS The correlation of immune infiltrates and prognosis of m6A RNA methylation regulators in lung cancer was comprehensively analyzed by bioinformatics, based on TCGA database. RESULTS Some m6A RNA methylation regulators were differentially expressed in lung squamous carcinoma(LUSC) and lung adenocarcinoma(LUAD). However, ALKBH5 was significantly high expressed only in LUSC, METTL3 and YTHDF3 were significantly high expressed only in LUAD, and HNRNPA2B1 was associated with the expression of YTHDC1 in LUSC and RBM15 in LUAD. By consistent clustering of 18 m6A methylation regulators, it was found that there was no statistically significant difference of the overall survival(OS) among different subtypes of LUSC. In LUAD, there was no significant difference in the expression of PD-1 and PD-L1 between cancer and adjacent tissues, and there was also no significant correlation with m6A methylation regulators. Cluster analysis revealed that m6A methylation regulators played an important role in the immune microenvironment of LUAD, in which the expression of PD-L1 decreased and the infiltration of immune cells was higher in Cluster 2, but the OS was longer than that in Cluster 1. Cluster 2 was more correlated with dendritic cell resting, mast cell resting, T cells gamma delta. The short OS of Cluster 1 may be related to the G2M checkpoint, E2F pathway, MYC pathway, MTORC1 pathway, Wnt/beta-catenin pathway, as well as the higher level of dendritic cells activated, macrophages M1 and T cells follicular helper. Univariate Cox analysis showed that four methylated binding proteins were associated with prognosis, IGF2BP3, HNRNPA2B1 and IGF2BP2 were risk factors and YTHDF2 was protection factor. CONCLUSION m6A RNA methylation regulators are closely related to the immune infiltration and prognosis of LUAD.