Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene
Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene
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DOI：
10.1093/jnci/dji204
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发表时间：
2005-08-03
影响因子：
10.3
通讯作者：
Markowitz, SD
中科院分区：
文献类型：
--
作者：
Chen, WD;Han, ZJ;Markowitz, SD
背景DNA甲基化增加是一种表观遗传改变，在人类癌症中很常见，通常与转录沉默有关。异常甲基化DNA也被认为是一种潜在的肿瘤标志物。然而，在正常上皮中转录沉默的基因，如波形蛋白，直到现在还没有被认为是癌症相关异常甲基化的靶点，也没有被用作癌症标志物。研究方法：我们应用甲基化特异性聚合酶链反应的波形蛋白基因，这是转录沉默在正常的结肠细胞，并比较甲基化的波形蛋白外显子-1在癌组织和粪便DNA从结肠癌患者与对照组样本从健康受试者。结果：46例正常结肠组织中45例Vimentin外显子1序列未甲基化。相比之下，波形蛋白外显子-1序列甲基化在83%（38/46）和53%（57/107）的肿瘤从两个独立收集的结肠癌患者组。当在另一组结肠癌患者的粪便DNA中作为结肠癌检测的标志物进行评估时，在94名患者中的43名患者的粪便DNA中检测到异常波形蛋白甲基化，灵敏度为46%（95%置信区间[Cl] = 35%至56%）。检测I期和II期癌症的敏感性为43%（60例患者中的26例）（95%CI = 31%至57%）。只有10%（198例患者中的20例）来自无癌症个体的对照粪便DNA样本检测为波形蛋白甲基化阳性，特异性为90%（95%CI = 85%至94%）。结论：非转录波形蛋白基因内外显子1序列的异常甲基化是结肠癌的一种新的分子生物标志物，可以在粪便DNA中成功检测到，以识别近一半的结肠癌患者。
Background. Increased DNA methylation is an epigenetic alteration that is common in human cancers and is often associated with transcriptional silencing. Aberrantly methylated DNA has also been proposed as a potential tumor marker. However, genes such as vimentin, which are transcriptionally silent in normal epithelium, have not until now been considered as targets for cancer-associated aberrant methylation and for use as cancer markers. Methods: We applied methylation-specific polymerase chain reaction to the vimentin gene, which is transcriptionally silent in normal colonocytes, and compared methylation of vimentin exon-1 in cancer tissues and in fecal DNA from colon cancer patients versus control samples from healthy subjects. Results: Vimentin exon-1 sequences were unmethylated in 45 of 46 normal colon tissues. In contrast, vimentin exon-1 sequences were methylated in 83% (38 of 46) and 53% (57 of 107) of tumors from two independently collected groups of colon cancer patients. When evaluated as a marker for colon cancer detection in fecal DNA from another set of colon cancer patients, aberrant vimentin methylation was detected in fecal DNA from 43 of 94 patients, for a sensitivity of 46% (95% confidence interval [Cl] = 35% to 56%). The sensitivity for detecting stage I and II cancers was 43% (26 of 60 case patients) (95% Cl = 31% to 57%). Only 10% (20 of 198 case patients) of control fecal DNA samples from cancer-free individuals tested positive for vimentin methylation, for a specificity of 90% (95% Cl = 85% to 94%). Conclusions: Aberrant methylation of exon-1 sequences within the nontranscribed vimentin gene is a novel molecular biomarker of colon cancer and can be successfully detected in fecal DNA to identify nearly half of individuals with colon cancer.