Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.
Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.
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DOI：
10.1002/ijc.30781
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发表时间：
2017-08-15
影响因子：
6.4
通讯作者：
Wentzensen N
中科院分区：
文献类型：
--
作者：
Clarke MA;Luhn P;Gage JC;Bodelon C;Dunn ST;Walker J;Zuna R;Hewitt S;Killian JK;Yan L;Miller A;Schiffman M;Wentzensen N
人类乳头瘤病毒(HPV)检测最近被引入作为宫颈癌筛查细胞学的替代方法。然而，由于大多数HPV感染是在不引起临床相关损害的情况下清除的，因此需要额外的分诊测试来确定哪些妇女有患癌症的高风险。我们对良性HPV16感染和组织学证实的宫颈上皮内瘤变3级(CIN3)和癌症患者的福尔马林固定的石蜡包埋组织样本进行了DNA甲基化分析，该芯片覆盖了800多个基因中的1,500个CpG位点。使用t检验比较各个CpG位点的甲基化水平，并通过计算p值来总结结果。通过DNA甲基化分析确定了12个候选基因(ADCYAP1、ASCL1、ATP10、CADM1、DCC、DBC1、HS3ST2、MOS、MYOD1、SOX1、SOX17和TMEFF2)，另外选择了另外三个从文献中确定的基因(EPB41L3、MAL、miR-124)，用于在一组独立的167个液体细胞学标本中进行验证，使用焦解测序法和有针对性的下一代亚硫酸氢盐测序。在15个候选基因标记中，有10个的曲线下面积(AUC值)为0.75，用于区分高度鳞状上皮内病变或更严重的鳞状上皮内病变(≥+)。总体而言，无论甲基化检测方法如何，SOX1、DCC和EPB41L3的AUC值均为≥0.80，显示出最好的区分性。除了验证文献中的候选标记物(例如，SOX1和EPB41L3)外，我们还确定了可被考虑用于检测宫颈癌前病变和癌症的新标记物，并值得在前瞻性研究中进一步验证。
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3 (CIN3), and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17, and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL, miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from <HSIL cytology using at least one assay. Overall, SOX1, DCC, and EPB41L3 showed the best discrimination with AUC values of ≥0.80, irrespective of methylation detection assay. In addition to verifying candidate markers from the literature (e.g., SOX1 and EPB41L3), we identified novel markers that may be considered for detection of cervical precancer and cancer and warrant further validation in prospective studies.
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影响因子：
3.7
作者：
Ashktorab, Hassan;Rahi, Hamed;Brim, Hassan
通讯作者：
Brim, Hassan
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影响因子：
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影响因子：
4.2
作者：
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Lee, Myeong-Sok
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作者：
Malik, Manzoor Ahmad;Gupta, Annapurna;Mittal, Balraj
通讯作者：
Mittal, Balraj
筛选样品中DNA甲基化HPV分类器分类器的验证。
影响因子：
6.4
作者：
Lorincz AT;Brentnall AR;Scibior-Bentkowska D;Reuter C;Banwait R;Cadman L;Austin J;Cuzick J;Vasiljević N
通讯作者：
Vasiljević N