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m6A/m5C 调控基因在早期肺腺癌中的预后价值和基因组特征。

Prognostic Value and Genome Signature of m6A/m5C Regulated Genes in Early-Stage Lung Adenocarcinoma.

机构信息

Lung Cancer Center, Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, China.

Lung Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.

出版信息

Int J Mol Sci. 2023 Mar 30;24(7):6520. doi: 10.3390/ijms24076520.


DOI:10.3390/ijms24076520
PMID:37047493
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10095361/
Abstract

RNA modifications implicate pathological and prognosis significance in cancer development and progression, of which, m6A and m5C are representative regulators. These RNA modifications could produce effects on the function of other RNA by regulating gene expression. Thus, in this study, we aimed to explore the correlation between m6A/m5C regulators and early-stage lung adenocarcinoma (LUAD). Only the early-stage LUAD samples were included in this investigation, and the RNA-seq dataset of The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate the expression of 37 m6A/m5C regulated genes. Based on the expression level of these 37 genes, early-stage LUAD patients were divided into 2 clusters, which were performed by consensus clustering, and the m6A/m5C subtypes had significantly different prognostic outcomes ( < 0.001). Cluster1, which has a better prognosis, was characterized by the C3 (inflammatory) immune subtype, low immune infiltration, chemokine expression, major histocompatibility complex (MHC) expression, and immune checkpoint molecule expression. Furthermore, compared with cluster1, cluster2 showed a T cell exhaustion state, characterized by a high expression of immune checkpoint genes, and immune cells, such as T cells, CD8+ T cells, cytotoxic lymphocytes, NK cells, and so on. In addition, patients in cluster2 were with high tumor mutational burden (TMB) and numerous significant mutated oncogene and tumor suppressor genes, such as WNT10B, ERBB4, SMARCA4, TP53, and CDKN2A ( < 0.001). A total of 19 genes were mostly related to the prognosis of LUAD and were upregulated in cluster2 ( < 0.05), showing a positive correlation with the mRNA expression of 37 m6A/m5C regulated genes. The predictive risk model was constructed using Cox and LASSO (least absolute shrinkage and selection operator) regression analysis. Finally, a seven-gene m6A/m5C risk model, comprising of METTL3, NPLOC4, RBM15, YTHDF1, IGF2BP1, NSUN3, and NSUN7, was constructed to stratify the prognosis of early-stage LUAD ( = 0.0049, AUC = 0.791). The high-risk score was associated with a poorer prognosis. This model was also validated using two additional GEO datasets: GSE72094 ( = 0.011, AUC = 0.736) and GSE50081 ( = 0.012, AUC = 0.628). In summary, it was established that the m6A/m5C-regulated genes performed a crosstalk function in the mRNA expression of early-stage LUAD. By interacting with other mRNA genes, m6A/m5C modification disturbs DNA replication and the tumor immune microenvironment (TIME). The seven-gene risk model may be a critical tool for the prognostic assessment of early-stage LUAD.

摘要

RNA 修饰在癌症的发生和发展中暗示了病理和预后意义,其中 m6A 和 m5C 是代表性的调节剂。这些 RNA 修饰可以通过调节基因表达对其他 RNA 的功能产生影响。因此,在这项研究中,我们旨在探讨 m6A/m5C 调节剂与早期肺腺癌 (LUAD) 之间的相关性。本研究仅纳入早期 LUAD 样本,并利用癌症基因组图谱 (TCGA) 队列的 RNA-seq 数据集评估 37 个 m6A/m5C 调控基因的表达。基于这些 37 个基因的表达水平,早期 LUAD 患者通过共识聚类分为 2 个聚类,m6A/m5C 亚型具有明显不同的预后结果(<0.001)。预后较好的聚类 1 特征为 C3(炎症)免疫亚型,免疫浸润低,趋化因子表达、主要组织相容性复合体 (MHC) 表达和免疫检查点分子表达低。此外,与聚类 1 相比,聚类 2 表现出 T 细胞耗竭状态,特征是免疫检查点基因高表达,以及免疫细胞如 T 细胞、CD8+T 细胞、细胞毒性淋巴细胞、NK 细胞等表达增加。此外,聚类 2 患者具有较高的肿瘤突变负担 (TMB) 和大量显著突变的致癌基因和肿瘤抑制基因,如 WNT10B、ERBB4、SMARCA4、TP53 和 CDKN2A(<0.001)。共有 19 个基因与 LUAD 的预后密切相关,在聚类 2 中上调(<0.05),与 37 个 m6A/m5C 调控基因的 mRNA 表达呈正相关。使用 Cox 和 LASSO(最小绝对收缩和选择算子)回归分析构建预测风险模型。最后,构建了一个由 METTL3、NPLOC4、RBM15、YTHDF1、IGF2BP1、NSUN3 和 NSUN7 组成的 7 基因 m6A/m5C 风险模型,用于分层早期 LUAD 的预后(=0.0049,AUC=0.791)。高风险评分与预后不良相关。该模型还使用另外两个 GEO 数据集进行了验证:GSE72094(=0.011,AUC=0.736)和 GSE50081(=0.012,AUC=0.628)。总之,已经证实 m6A/m5C 调控基因在早期 LUAD 的 mRNA 表达中发挥了串扰功能。通过与其他 mRNA 基因相互作用,m6A/m5C 修饰扰乱了 DNA 复制和肿瘤免疫微环境 (TIME)。该 7 基因风险模型可能是评估早期 LUAD 预后的重要工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0352/10095361/8e6500fd3699/ijms-24-06520-g008.jpg
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