Background/Objectives: DNA methylation is a key epigenetic process that regulates gene expression and is often disrupted in colorectal cancer (CRC). Aberrant methylation of promoter CpG islands can silence tumor suppressor genes and drive tumorigenesis. A subset of CRCs exhibits the CpG Island Methylator Phenotype (CIMP), characterized by widespread hypermethylation and distinct clinical outcomes. Identifying genes whose expression is epigenetically regulated by methylation is important for prioritizing candidate biomarkers and therapeutic targets in CRC. Methods: We developed and compared a series of computational approaches to identify genes whose expression is regulated by DNA methylation in The Cancer Genome Atlas (TCGA) cohort of Colon Adenocarcinoma (COAD) patients. Samples were stratified according to their CpG Island Methylator Phenotype (CIMP) level to capture distinct epigenetic subgroups. The proposed framework integrates methylation and transcriptomic data to systematically detect methylation–expression associations indicative of epigenetic regulation. Results: The best-performing method identified gene sets strongly associated with promoter methylation–expression relationships and enriched for pathways relevant to colorectal cancer progression and patient stratification. To evaluate the robustness and transferability of the approach, it was further validated on independent datasets, including Stomach Adenocarcinoma (STAD), Glioblastoma Multiforme (GBM), and Mesothelioma (MESO), supporting its robustness and potential generalizability across multiple tumor types. Conclusions: Our study highlights the potential of computational pipelines to uncover epigenetically regulated genes in colorectal cancer. The identified candidate genes provide a hypothesis-generating foundation for refining molecular stratification and guiding future studies aimed at epigenetic biomarker discovery and therapeutic hypothesis development.
背景/目的：DNA甲基化是调控基因表达的关键表观遗传过程，在结直肠癌中常出现异常。启动子CpG岛的异常甲基化可导致抑癌基因沉默并驱动肿瘤发生。部分结直肠癌表现出CpG岛甲基化表型（CIMP），其特征是广泛的甲基化及独特的临床结局。识别受甲基化表观遗传调控的基因，对于筛选结直肠癌候选生物标志物和治疗靶点具有重要意义。方法：我们在癌症基因组图谱结肠腺癌队列中开发并比较了一系列计算方法，以鉴定受DNA甲基化调控表达的基因。根据CpG岛甲基化表型水平对样本进行分层，以捕捉不同的表观遗传亚群。该框架整合甲基化与转录组数据，系统性地检测指示表观遗传调控的甲基化-表达关联。结果：性能最佳的方法鉴定出与启动子甲基化-表达关系密切相关的基因集，这些基因集富集于与结直肠癌进展和患者分层相关的通路。为评估该方法的稳健性和可迁移性，我们在独立数据集（包括胃腺癌、多形性胶质母细胞瘤和间皮瘤）中进一步验证，支持其在不同肿瘤类型间的稳健性和潜在普适性。结论：我们的研究凸显了计算流程在揭示结直肠癌表观遗传调控基因方面的潜力。所鉴定的候选基因为完善分子分层提供了假设生成基础，并指导未来针对表观遗传生物标志物发现和治疗假设开发的研究。
肿瘤(癌症)患者之家