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通过检测血清DNA中异常的启动子甲基化来预测肝细胞癌

Predicting hepatocellular carcinoma by detection of aberrant promoter methylation in serum DNA.

作者信息

Zhang Yu-Jing, Wu Hui-Chen, Shen Jing, Ahsan Habibul, Tsai Wei Yann, Yang Hwai-I, Wang Li-Yu, Chen Shu-Yuan, Chen Chien-Jen, Santella Regina M

机构信息

Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, New York 10032, USA.

出版信息

Clin Cancer Res. 2007 Apr 15;13(8):2378-84. doi: 10.1158/1078-0432.CCR-06-1900.

Abstract

PURPOSE

Most hepatocellular carcinomas (HCC) are diagnosed at an advanced stage. Hypermethylation of CpG islands in promoter regions is now recognized as an important early event in carcinogenesis and detection of methylated DNA has been suggested as a potential biomarker for early detection of cancer. There are no studies on epigenetic changes in samples from HCC patients before diagnosis. We explored the possible diagnostic value of aberrant promoter hypermethylation of three tumor suppressor genes in serum DNA for early detection of HCC.

EXPERIMENTAL DESIGN

Aberrant promoter hypermethylation was investigated in DNA isolated from the serum of 50 HCC patients who provided repeated blood samples before diagnosis and 50 controls enrolled in a cancer screen program in Taiwan. Methylation-specific PCR was used to determine the methylation status of p16, p15, and ras association domain family 1A (RASSF1A).

RESULTS

Among cases, aberrant methylation was found in serum DNA 1 to 9 years before clinical HCC diagnosis. RASSF1A had the highest frequency of hypermethylation with 35 (70%) cases having at least one positive sample compared with 22 (44%) for p16 and 12 (22%) for p15. Six subjects were hypermethylation negative for all three genes. For the 50 controls, promoter hypermethylation was found in three and two subjects for RASSF1A and p16, respectively; none had methylation of p15. A receiver operating characteristic curve that included clinical risk factors (age, HBsAg status, anti-hepatitis C virus status, smoking, and alcohol status) and hypermethylation biomarkers gave an overall predictive accuracy of 89% with sensitivity and specificity 84% and 94%, respectively.

CONCLUSIONS

The analysis of epigenetic changes on RASSF1A, p16, and p15 tumor suppressor genes in serum DNA may be a valuable biomarkers for early detection in populations at high risk of HCC.

摘要

目的

大多数肝细胞癌(HCC)在晚期才被诊断出来。启动子区域CpG岛的高甲基化现已被认为是致癌过程中的一个重要早期事件,甲基化DNA的检测已被提议作为癌症早期检测的潜在生物标志物。目前尚无关于HCC患者诊断前样本表观遗传变化的研究。我们探讨了血清DNA中三个抑癌基因启动子异常高甲基化对HCC早期检测的可能诊断价值。

实验设计

对50例在诊断前提供多次血样的HCC患者血清中分离的DNA以及台湾癌症筛查项目中纳入的50名对照者进行启动子异常高甲基化研究。采用甲基化特异性PCR确定p16、p15和Ras关联结构域家族1A(RASSF1A)的甲基化状态。

结果

在病例中,临床HCC诊断前1至9年血清DNA中发现异常甲基化。RASSF1A的高甲基化频率最高,35例(70%)至少有一个阳性样本,相比之下,p16为22例(44%),p15为12例(22%)。6名受试者这三个基因的甲基化均为阴性。对于50名对照者,RASSF1A和p16分别在3名和2名受试者中发现启动子高甲基化;p15均未发生甲基化。包含临床危险因素(年龄、乙肝表面抗原状态、抗丙型肝炎病毒状态、吸烟和饮酒状态)和高甲基化生物标志物的受试者工作特征曲线显示,总体预测准确率为89%,敏感性和特异性分别为84%和94%。

结论

血清DNA中RASSF1A、p16和p15抑癌基因的表观遗传变化分析可能是HCC高危人群早期检测的有价值生物标志物。

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