Abnormal DNA methylation is considered a vital hallmark to regulate gene expression and influence the development and progression of colorectal cancer (CRC). Although CRC‐related methylation prognostic models have been developed, their clinical application is limited due to the lack of external validation and extension to other survival evaluation indicators. Therefore, this study aimed to develop and validate novel methylation prognostic models correlated with different survival indicators for individualized prognosis prediction for CRC patients. The prognostic‐related CpG sites of methylation‐driven genes screened by the MethylMix algorithm were identified and validated in The Cancer Genome Atlas (TCGA) CRC methylation data and our methylation data. The prognostic models correlated with different survival evaluation indicators (overall survival [OS] and disease‐free survival [DFS]) were developed and validated in the TCGA CRC dataset (N = 376) and our independent CRC dataset (N = 227). We utilized the combination of selected 3‐CpG methylation sites in three genes (DAPP1, FAM3D, and PIGR) to construct a prognostic risk‐score model. In the training dataset, Kaplan–Meier survival analysis demonstrated that high‐risk patients had significantly poorer survival than low‐risk patients (p_OS = .0014; p_DFS < .001). Then, the 3‐CpG methylation signature was successfully validated as an independent predictor in the testing data set (p_OS = .016; p_DFS = .016). A prognostic nomogram was constructed and validated. Additionally, mediation analysis revealed the direct effect of the methylation signature on CRC prognosis (p_OS = 9.149e−06; p_DFS = .001). In summary, our study revealed that the 3‐CpG methylation signature might be a potential prognostic indicator to facilitate individualized survival prediction for CRC patients.

中文翻译：

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基于不同生存指标的结直肠癌 3-CpG 甲基化预后特征的开发和验证

异常的 DNA 甲基化被认为是调节基因表达和影响结直肠癌 (CRC) 发展和进展的重要标志。尽管已经开发了 CRC 相关的甲基化预后模型，但由于缺乏外部验证和扩展到其他生存评估指标，其临床应用受到限制。因此，本研究旨在开发和验证与不同生存指标相关的新型甲基化预后模型，用于 CRC 患者的个体化预后预测。通过 MethylMix 算法筛选的甲基化驱动基因的预后相关 CpG 位点在癌症基因组图谱 (TCGA) CRC 甲基化数据和我们的甲基化数据中得到鉴定和验证。N  = 376）和我们的独立 CRC 数据集（N  = 227）。我们利用三个基因（DAPP1、FAM3D和PIGR）中选定的 3-CpG 甲基化位点的组合来构建预后风险评分模型。在训练数据集中，Kaplan-Meier 生存分析表明，高风险患者的生存率明显低于低风险患者（p _OS  = .0014；p _DFS  < .001）。然后，3-CpG 甲基化特征被成功验证为测试数据集中的独立预测因子（p _OS  = .016；p _DFS = .016）。构建并验证了预后列线图。此外，中介分析揭示了甲基化特征对 CRC 预后的直接影响（p _OS  = 9.149e-06；p _DFS  = .001）。总之，我们的研究表明，3-CpG 甲基化特征可能是促进 CRC 患者个体化生存预测的潜在预后指标。