Circulating cell-free DNA-based epigenetic assay can detect early breast cancer.
Circulating cell-free DNA-based epigenetic assay can detect early breast cancer.
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DOI：
10.1186/s13058-016-0788-z
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发表时间：
2016-12-19
期刊：
影响因子：
--
通讯作者：
Toi M
中科院分区：
文献类型：
--
作者：
Uehiro N;Sato F;Pu F;Tanaka S;Kawashima M;Kawaguchi K;Sugimoto M;Saji S;Toi M
循环无细胞DNA（cfDNA）最近被认为是癌症进展、治疗反应和耐药性的生物标志物的资源。然而，很少有人证明cfDNA对癌症早期检测的有用性。尽管cfDNA中的异常DNA甲基化已经报道了十多年，但其诊断准确性对于癌症筛查仍然不令人满意。因此，本研究的目的是开发一种高灵敏度的cfDNA为基础的系统检测原发性乳腺癌（BC）使用表观遗传生物标志物和数字PCR技术。基于阵列的全基因组DNA甲基化分析使用56个显微切割的乳腺组织标本，34个细胞系和29个健康志愿者（HV）的血液样本进行。选择用于BC检测的表观遗传标记，并建立具有所选标记的液滴数字甲基化特异性PCR（ddMSP）面板。通过支持向量机构建检测模型，并使用cfDNA样品进行评估。甲基化阵列分析鉴定了12个新的用于检测BC的表观遗传标记（JAK 3、RASGRF 1、CPXM 1、SHF、DNM 3、CAV 2、HOXA 10、B3 GNT 5、ST 3GAL 6、DACH 1、P2 RX 3和chr 8：2357 - 2595）。我们还选择了四个内部对照标记（CREM，GLYATL 3，ELMOD 3和KLF 9），这些标记使用公共数据库被鉴定为不常改变的基因。开发了使用这16个标志物的ddMSP组，并使用含有来自80个HV和87个癌症患者的cfDNA样品的训练数据集构建了检测模型。最佳检测模型采用了四种甲基化标志物（RASGRF 1，CPXM 1，HOXA 10和DACH 1）和两个参数（cfDNA浓度和12种甲基化标志物的平均值），并在53名HV和58名BC患者的独立数据集中进行了验证。在训练和验证数据集中，癌症-正常区分的受试者工作特征曲线下面积分别为0.916和0.876。模型的敏感性和特异性分别为0.862（0-I期0.846，IIA期0.862，IIB-III期0.818，转移性BC期0.935）和0.827。我们的基于表观遗传标记的系统以高准确度区分了BC患者和HV。由于使用该系统检测早期BC与乳房X线摄影筛查相当，因此该系统作为筛查BC的可选方法将是有益的。本文的在线版本（doi：10.1186/s13058-016-0788-z）包含补充材料，可供授权用户使用。
Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC. The online version of this article (doi:10.1186/s13058-016-0788-z) contains supplementary material, which is available to authorized users.
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DOI：
10.1186/s12905-016-0351-1
发表时间：
2016-11-18
期刊：
BMC women's health
影响因子：
--
作者：
Lee K;Kim H;Lee JH;Jeong H;Shin SA;Han T;Seo YL;Yoo Y;Nam SE;Park JH;Park YM
通讯作者：
Park YM
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
2.6
作者：
Brooks, Jennifer D.;Cairns, Paul;Shore, Roy E.;Klein, Catherine B.;Wirgin, Isaac;Afanasyeva, Yelena;Zeleniuch-Jacquotte, Anne
通讯作者：
Zeleniuch-Jacquotte, Anne
影响因子：
--
作者：
Chen K;Wu K;Gormley M;Ertel A;Wang J;Zhang W;Zhou J;Disante G;Li Z;Rui H;Quong AA;McMahon SB;Deng H;Lisanti MP;Wang C;Pestell RG
通讯作者：
Pestell RG
DOI：
10.1186/bcr3375
发表时间：
2013-01-15
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Kloten V;Becker B;Winner K;Schrauder MG;Fasching PA;Anzeneder T;Veeck J;Hartmann A;Knüchel R;Dahl E
通讯作者：
Dahl E