Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls.
Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls.
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白细胞 DNA 甲基化特征可将胰腺癌患者与健康对照区分开来。
DOI：
10.1371/journal.pone.0018223
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发表时间：
2011-03-24
期刊：
影响因子：
3.7
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Pedersen KS;Bamlet WR;Oberg AL;de Andrade M;Matsumoto ME;Tang H;Thibodeau SN;Petersen GM;Wang L
胰腺腺癌（PaC）是最难治疗的肿瘤之一。这在很大程度上是由于诊断较晚。为了确定早期检测的生物标志物，我们在一项两期研究中检测了PaC病例和对照组之间白细胞DNA的DNA甲基化差异。在第一阶段，我们测量了132名从不吸烟的PaC患者和60名从不吸烟的健康对照者treatment-naïve白细胞DNA中1505个CpG位点的甲基化水平。我们发现110个CpG位点存在显著性差异（错误发现率<0.05）。在第二阶段，我们对240例PaC患者和240例匹配对照的96个第一阶段选择的CpG位点中的88个进行了测试和验证（p≤0.05）。使用惩罚逻辑回归，我们建立了一个由五个CpG位点（IL10_P348, LCN2_P86, ZAP70_P220, AIM2_P624, TAL1_P817）组成的预测模型，该模型将PaC患者与对照组区分出来（I期c统计量= 0.85，II期为0.76）。有趣的是，仅一个CpG位点（LCN2_P86）就可以将可切除的患者与对照组区分开来（I期c统计值= 0.78，II期为0.74）。我们还进行了甲基化数量性状位点（methQTL）分析，发现了三个CpG位点（AGXT_P180_F, ALOX12_E85_R, JAK3_P1075_R），其中甲基化水平与单核苷酸多态性（snp）显著相关（错误发现率<0.05）。我们的研究结果表明，易于获得的白细胞DNA的表观遗传变异，表现为可重复的甲基化差异，可用于检测PaC患者。某些CpG位点的甲基化差异部分可归因于遗传变异。这项研究有力地支持了未来使用白细胞DNA进行全表观基因组关联研究，以发现人类疾病的生物标志物。
Pancreatic adenocarcinoma (PaC) is one of most difficult tumors to treat. Much of this is attributed to the late diagnosis. To identify biomarkers for early detection, we examined DNA methylation differences in leukocyte DNA between PaC cases and controls in a two-phase study. In phase I, we measured methylation levels at 1,505 CpG sites in treatment-naïve leukocyte DNA from 132 never-smoker PaC patients and 60 never-smoker healthy controls. We found significant differences in 110 CpG sites (false discovery rate <0.05). In phase II, we tested and validated 88 of 96 phase I selected CpG sites in 240 PaC cases and 240 matched controls (p≤0.05). Using penalized logistic regression, we built a prediction model consisting of five CpG sites (IL10_P348, LCN2_P86, ZAP70_P220, AIM2_P624, TAL1_P817) that discriminated PaC patients from controls (C-statistic = 0.85 in phase I; 0.76 in phase II). Interestingly, one CpG site (LCN2_P86) alone could discriminate resectable patients from controls (C-statistic = 0.78 in phase I; 0.74 in phase II). We also performed methylation quantitative trait loci (methQTL) analysis and identified three CpG sites (AGXT_P180_F, ALOX12_E85_R, JAK3_P1075_R) where the methylation levels were significantly associated with single nucleotide polymorphisms (SNPs) (false discovery rate <0.05). Our results demonstrate that epigenetic variation in easily obtainable leukocyte DNA, manifested by reproducible methylation differences, may be used to detect PaC patients. The methylation differences at certain CpG sites are partially attributable to genetic variation. This study strongly supports future epigenome-wide association study using leukocyte DNA for biomarker discovery in human diseases.
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影响因子：
3.7
作者：
Boks MP;Derks EM;Weisenberger DJ;Strengman E;Janson E;Sommer IE;Kahn RS;Ophoff RA
通讯作者：
Ophoff RA
影响因子：
15.8
作者：
Faca VM;Song KS;Wang H;Zhang Q;Krasnoselsky AL;Newcomb LF;Plentz RR;Gurumurthy S;Redston MS;Pitteri SJ;Pereira-Faca SR;Ireton RC;Katayama H;Glukhova V;Phanstiel D;Brenner DE;Anderson MA;Misek D;Scholler N;Urban ND;Barnett MJ;Edelstein C;Goodman GE;Thornquist MD;McIntosh MW;DePinho RA;Bardeesy N;Hanash SM
通讯作者：
Hanash SM
胰腺癌的早期诊断：中性粒细胞明胶酶相关的脂肪蛋白作为胰腺上皮内肿瘤的标志。
影响因子：
8.8
作者：
Moniaux N;Chakraborty S;Yalniz M;Gonzalez J;Shostrom VK;Standop J;Lele SM;Ouellette M;Pour PM;Sasson AR;Brand RE;Hollingsworth MA;Jain M;Batra SK
通讯作者：
Batra SK
影响因子：
2.3
作者：
Poch, Bertram;Lotspeich, Errki;Gansauge, Frank
通讯作者：
Gansauge, Frank
影响因子：
3.6
作者：
Jansen, M;Fukushima, N;Goggins, M
通讯作者：
Goggins, M