Table_7_RNA m6A Methylation Regulators Subclassify Luminal Subtype in Breast Cancer.xlsx

RNA N6-methyladenosine (m6A) methylation is the most prevalent epitranscriptomic modification in mammals, with a complex and fine-tuning regulatory system. Recent studies have illuminated the potential of m6A regulators in clinical applications including diagnosis, therapeutics, and prognosis. Based on six datasets of breast cancer in The Cancer Genome Atlas (TCGA) database and two additional proteomic datasets, we provide a comprehensive view of all the known m6A regulators in their gene expression, copy number variations (CNVs), DNA methylation status, and protein levels in breast tumors and their association with prognosis. Among four breast cancer subtypes, basal-like subtype exhibits distinct expression and genomic alteration in m6A regulators from other subtypes. Accordingly, four representative regulators (IGF2BP2, IGF2BP3, YTHDC2, and RBM15) are identified as basal-like subtype-featured genes. Notably, luminal A/B samples are subclassified into two clusters based on the methylation status of those four genes. In line with its similarity to basal-like subtype, cluster1 shows upregulation in immune-related genes and cell adhesion molecules, as well as an increased number of tumor-infiltrating lymphocytes. Besides, cluster1 has worse disease-free and progression-free survival, especially among patients diagnosed with stage II and luminal B subtype. Together, this study highlights the potential functions of m6A regulators in the occurrence and malignancy progression of breast cancer. Given the heterogeneity within luminal subtype and high risk of recurrence and metastasis in a portion of patients, the prognostic stratification of luminal A/B subtypes utilizing basal-featured m6A regulators may help to improve the accuracy of diagnosis and therapeutics of breast cancer.

RNA N6-甲基腺苷（m6A）甲基化是哺乳动物中最为普遍的表观转录组修饰，其调控系统复杂且精细。近期研究揭示了m6A调控因子在诊断、治疗及预后等临床应用中的潜力。本研究基于癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库中的6套乳腺癌数据集与2套额外的蛋白质组数据集，全面分析了所有已知m6A调控因子的基因表达、拷贝数变异（copy number variations, CNVs）、DNA甲基化状态及蛋白质水平在乳腺肿瘤中的特征，并阐明其与预后的关联。在四种乳腺癌亚型中，基底样亚型的m6A调控因子在表达与基因组改变方面与其他亚型存在显著差异。据此，我们鉴定出4个代表性调控因子（IGF2BP2、IGF2BP3、YTHDC2及RBM15）作为基底样亚型特征基因。值得注意的是，管腔A/B型样本可基于这4个基因的甲基化状态被划分为两个聚类。与基底样亚型相似，聚类1的免疫相关基因与细胞黏附分子表达上调，肿瘤浸润淋巴细胞数量亦增加。此外，聚类1的无病生存期与无进展生存期更差，尤其在诊断为II期及管腔B亚型的患者中更为显著。综上，本研究凸显了m6A调控因子在乳腺癌发生与恶性进展中的潜在功能。鉴于管腔亚型内部存在异质性，且部分患者存在较高的复发与转移风险，利用基底样特征m6A调控因子对管腔A/B亚型进行预后分层，或有助于提升乳腺癌诊断与治疗的精准性。