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N6-甲基腺苷甲基化图谱将乳腺癌分为具有不同免疫特征的两个亚型。

The N6-methyladenosine methylation landscape stratifies breast cancer into two subtypes with distinct immunological characteristics.

机构信息

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

出版信息

Clin Exp Pharmacol Physiol. 2024 Jul;51(7):e13875. doi: 10.1111/1440-1681.13875.

Abstract

N6-methyladenosine (m6A) methylation modification affects the tumorigenesis and metastasis of breast cancer (BC). This study investigated the association between m6A regulator-mediated methylation modification patterns and characterization of the tumour microenvironment in BC, as well as their prognostic importance. Public gene expression data and clinical annotations were collected from The Cancer Genome Atlas (TCGA) database, the Gene Expression Omnibus website and the METABRIC program. We analysed the genetic expression, gene-gene interactions, gene mutations and copy number variations using R software. The data were screened for risk genes using the Cox risk regression model, and we developed an algorithm for risk score and its predictive value. Compared to adjacent normal tissue, we identified 16 differentially expressed m6A regulators in BC, including six writers and 10 readers. Under unsupervised clustering, two distinguished modification patterns were identified, cluster C1 and C2. Compared to m6A cluster C2, cluster C1 was found to be more involved in immune-related pathways, with a relatively higher immune score and stromal score (P < 0.05). Patients were divided into two groups based on their risk scores for survival analysis. The patients in the high-risk score group had significantly worse overall survival than patients in the low-risk score group, (P < 0.0001). The TCGA database validation revealed the same prognostic tendency. In summary, our study showed distinct m6A regulator modification patterns contribute to the immunological heterogeneity and diversity of BC. The development of m6A gene signatures and the m6A score aid in the prognostic prediction of patients with BC.

摘要

N6-甲基腺苷(m6A)甲基化修饰影响乳腺癌(BC)的发生和转移。本研究探讨了 m6A 调节因子介导的甲基化修饰模式与 BC 肿瘤微环境特征之间的关联及其预后意义。从癌症基因组图谱(TCGA)数据库、基因表达综合网站和 METABRIC 计划中收集了公共基因表达数据和临床注释。我们使用 R 软件分析了遗传表达、基因-基因相互作用、基因突变和拷贝数变异。使用 Cox 风险回归模型筛选风险基因,并开发了风险评分及其预测值的算法。与相邻正常组织相比,我们在 BC 中鉴定出 16 个差异表达的 m6A 调节剂,包括 6 个写入器和 10 个读取器。在无监督聚类下,确定了两种不同的修饰模式,簇 C1 和 C2。与 m6A 簇 C2 相比,簇 C1 更多地参与了免疫相关途径,具有相对较高的免疫评分和基质评分(P<0.05)。根据风险评分对患者进行生存分析分组。高风险评分组患者的总生存率明显低于低风险评分组患者,(P<0.0001)。TCGA 数据库验证显示出相同的预后趋势。总之,我们的研究表明,不同的 m6A 调节因子修饰模式有助于 BC 的免疫异质性和多样性。m6A 基因特征和 m6A 评分的开发有助于预测 BC 患者的预后。

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