Oestrogen receptor expression in breast cancer (BC) cells is a marker of high cellular differentiation and allows the identification of two BC groups (ER-positive and ER-negative) that, although not completely homogeneous, differ in biological characteristics, clinical behaviour, and therapeutic options. The study, based on three publicly available EWAS (Epigenetic Wide Association Study) datasets, focuses on the comparison between these two groups of breast cancer using an epimutation score. The score is calculated not only based on the presence of the epimutation, but also on the deviation amplitude of the methylation outlier value. For each dataset, we performed a functional analysis based first on the functional gene region of each annotated gene (we aggregated the data per gene region TSS1500, TSS200, first-exon, and body-gene identified by the information from the Illumina Data Sheet), and then, we performed a pathway enrichment analysis through the REACTOME database based on the genes with the highest epimutation score. Thus, we blended our results and found common pathways for all three datasets. We found that a higher and significant epimutation score due to hypermethylation in ER-positive BC is present in the promoter region of the genes belonging to the SUMOylation pathway, the Notch pathway, the IFN-γsignalling pathway, and the deubiquitination protease pathway, while a higher and significant level of epimutation due to hypomethylation in ER-positive BC is present in the promoter region of the genes belonging to the ESR-mediated pathway. The presence of this state of promoter hypomethylation in the ESR-mediated signalling genes is consistent and coherent with an active signalling pathway mediated by oestrogen function in the group of ER-positive BC. The SUMOylation and Notch pathways are associated with BC pathogenesis and have been found to play distinct roles in the two BC subgroups. We speculated that the altered methylation profile may play a role in regulating signalling pathways with specific functions in the two subgroups of ER BC.
乳腺癌细胞中的雌激素受体表达是细胞高度分化的标志，可用于区分两类乳腺癌（ER阳性与ER阴性）。这两类肿瘤虽非完全同质，但在生物学特征、临床行为及治疗选择上存在差异。本研究基于三个公开的表观遗传全关联研究数据集，采用表观突变评分对这两类乳腺癌进行比较。该评分不仅依据表观突变的存在，还综合考虑甲基化异常值的偏离幅度。针对每个数据集，我们首先基于注释基因的功能区域（依据Illumina数据表信息，按TSS1500、TSS200、第一外显子和基因体区域进行数据整合）进行功能分析，随后通过REACTOME数据库对表观突变评分最高的基因进行通路富集分析。通过整合三个数据集的结果，我们发现了共有的通路特征。研究发现：在ER阳性乳腺癌中，SUMO化通路、Notch通路、IFN-γ信号通路及去泛素化蛋白酶通路相关基因的启动子区域，因高甲基化呈现显著升高的表观突变评分；而ESR介导通路相关基因的启动子区域，则因低甲基化呈现显著升高的表观突变水平。ESR介导信号基因启动子的低甲基化状态，与ER阳性乳腺癌组中雌激素功能介导的活跃信号通路具有一致性和连贯性。SUMO化与Notch通路均与乳腺癌发病机制相关，且在两类乳腺癌亚型中发挥不同作用。我们推测，这种甲基化谱的改变可能在ER阳性与阴性乳腺癌亚型中，对具有特定功能的信号通路调控发挥作用。
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