用于预测 II 期结直肠癌肿瘤复发的 DNA 甲基化特征。
A DNA methylation signature for the prediction of tumour recurrence in stage II colorectal cancer.
机构信息
Cancer Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China.
Institute of Clinical Sciences, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P. R. China.
出版信息
Br J Cancer. 2023 May;128(9):1681-1689. doi: 10.1038/s41416-023-02155-8. Epub 2023 Feb 24.
BACKGROUND
A major challenge in stage II colorectal carcinoma is to identify patients with increased risk of recurrence. Biomarkers that distinguish patients with poor prognosis from patients without recurrence are currently lacking. This study aims to develop a robust DNA methylation classifier that allows the prediction of recurrence and chemotherapy benefit in patients with stage II colorectal cancer. We performed a genome-wide DNA methylation capture sequencing in 243 stage II colorectal carcinoma samples and identified a relapse-specific DNA methylation signature consisting of eight CpG sites.
METHODS
Two hundred and forty-three patients with stage II CRC were enrolled in this study. In order to select differential methylation sites among recurrence and non-recurrence stage II CRC samples, DNA methylation profiles of 62 tumour samples including 31 recurrence and 31 nonrecurrence samples were analysed using the Agilent SureSelectXT Human Methyl-Seq, a comprehensive target enrichment system to analyse CpG methylation. Pyrosequencing was applied to quantify the methylation level of candidate DNA methylation sites in 243 patients. Least absolute shrinkage and selection operator (LASSO) method was employed to build the disease recurrence prediction classifier.
RESULTS
We identified a relapse-related DNA methylation signature consisting of eight CpG sites in stage II CRC by DNA methylation capture sequencing. The classifier showed significantly higher prognostic accuracy than any clinicopathological risk factors. The Kaplan-Meier survival curve showed an association of high-risk score with poor prognosis. In multivariate analysis, the signature was the most significant prognosis factor, with an HR of 2.80 (95% CI, 1.71-4.58, P < 0.001). The signature could identify patients who are suitable candidates for adjuvant chemotherapy.
CONCLUSIONS
An eight-CpG DNA methylation signature is a reliable prognostic and predictive tool for disease recurrence in patients with stage II CRC.
背景
在 II 期结直肠癌中，一个主要的挑战是识别具有高复发风险的患者。目前缺乏能够区分预后不良患者和无复发患者的生物标志物。本研究旨在开发一种稳健的 DNA 甲基化分类器，以预测 II 期结直肠癌患者的复发和化疗获益。我们对 243 例 II 期结直肠癌样本进行了全基因组 DNA 甲基化捕获测序，确定了一个由 8 个 CpG 位点组成的复发特异性 DNA 甲基化特征。
方法
本研究纳入了 243 例 II 期 CRC 患者。为了筛选复发和非复发 II 期 CRC 样本中的差异甲基化位点，使用 Agilent SureSelectXT Human Methyl-Seq（一种全面的靶向富集系统，用于分析 CpG 甲基化）对 62 例肿瘤样本（包括 31 例复发样本和 31 例非复发样本）的 DNA 甲基化谱进行了分析。在 243 例患者中应用焦磷酸测序定量候选 DNA 甲基化位点的甲基化水平。采用最小绝对收缩和选择算子（LASSO）方法构建疾病复发预测分类器。
结果
我们通过 DNA 甲基化捕获测序鉴定出 II 期 CRC 中与复发相关的 DNA 甲基化特征，由 8 个 CpG 位点组成。该分类器的预后准确性明显高于任何临床病理危险因素。Kaplan-Meier 生存曲线显示高危评分与预后不良相关。多因素分析显示，该特征是最显著的预后因素，HR 为 2.80（95%CI，1.71-4.58，P<0.001）。该特征可以识别适合辅助化疗的患者。
结论
8 个 CpG DNA 甲基化特征是 II 期结直肠癌患者疾病复发的可靠预后和预测工具。
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