Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.
Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.
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DOI：
10.1158/1940-6207.capr-13-0407
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Sapienza C
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文献类型：
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作者：
Cesaroni M;Powell J;Sapienza C
我们已经验证了先前报道的候选基因的DNA甲基化水平的差异，以区分结肠癌患者的正常结肠粘膜和非癌症个体的正常结肠粘膜。在这里，我们报告说，CpG位点的30个候选基因中的16个显示出显着差异的平均甲基化水平在24例癌症患者和24个对照组的正常结肠粘膜。在这些数据和另外66个CpG的数据上训练的支持向量机产生了18个基因签名，由10个经验证的候选基因加上8个另外的候选基因组成。该模型在40个样本的训练集中表现出96%的灵敏度和100%的特异性，并正确地对测试集中的所有8个样本进行分类。此外，我们发现在支持向量模型中的18个基因中的7个的结肠粘膜中的甲基化水平和外周血中的甲基化水平之间存在中等强相关性（Pearson系数r=0.253-0.722）。仅这七个基因就正确地分类了验证集中48名患者中的44名，并且从七个基因中的仅两个中选择的五个CpG正确地分类了发现集中48名患者中的41名。这些结果表明，甲基化生物标志物可能会被开发，至少，作为有用的客观和定量诊断补充结肠镜检查作为癌症筛查工具。这些数据还表明，与结肠镜检查相比，有可能监测侵入性更低的组织中生物标志物甲基化水平。
We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of colon cancer patients and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 cancer patients and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of 10 of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r=0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy.