Quantitative assessment of promoter methylation profiles in thyroid neoplasms
Quantitative assessment of promoter methylation profiles in thyroid neoplasms
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DOI：
10.1210/jc.2005-0313
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发表时间：
2005-07-01
影响因子：
5.8
通讯作者：
Umbricht, CB
中科院分区：
文献类型：
--
作者：
Hoque, MO;Rosenbaum, E;Umbricht, CB
内容：甲状腺肿瘤的细胞病理学评估需要癌症特异性分子标记物作为补充，因为大多数细胞学不确定结节的患者目前接受甲状腺切除术而没有明确的诊断。目的：本研究的目的是定量评估甲状腺肿瘤中启动子超甲基化及其与BRAF突变的关系。设计：在82个良性和恶性甲状腺肿瘤和5个甲状腺癌细胞系的队列中检测了Rassf 1A、TSHR、RAR-β 2、DAPK、S100、p16、CDH 1、CALCA、TIMP 3、TGF-β和GSTpi的定量超甲基化。研究在一家三级研究医院进行。患者：2000年至2003年在我们机构接受甲状腺肿瘤手术切除术的患者。干预措施：没有干预措施。主要结局指标：最终手术病理诊断是主要结局指标。结果：甲状腺肿瘤显示以下标志物的高甲基化：Rassf 1A、TSHR、RAR-β 2、DAPK、CDH 1、TIMP 3和TGF-β。在癌组织中，多个甲基化的趋势是明显的，在25%的增生、38%的腺瘤、48%的甲状腺癌和100%的细胞系中可检测到两个或更多个标记物的甲基化。标记物超甲基化的等级相关分析表明，这些标记物的子集是一致的表观遗传修饰，这可能反映了器官特异性调节过程。BRAF突变与RAR-beta 2呈正相关，与Rassf 1A呈负相关。结论：甲基化诱导的基因沉默可能影响甲状腺组织中多个基因，并随着甲状腺癌的进展而增加。对于细胞学不确定的甲状腺结节的诊断评估，需要在良性和恶性样本之间具有更好区分能力的其他标记物。
Context: Cancer-specific molecular markers are needed to supplement the cytopathological assessment of thyroid tumors, because a majority of patients with cytologically indeterminate nodules currently undergo thyroidectomy without a definitive diagnosis.Objective: The aim of this study was the quantitative assessment of promoter hypermethylation and its relation to the BRAF mutation in thyroid tumors.Design: Quantitative hypermethylation of Rassf1A, TSHR, RAR-beta 2, DAPK, S100, p16, CDH1, CALCA, TIMP3, TGF-beta, and GSTpi was tested on a cohort of 82 benign and malignant thyroid tumors and five thyroid cancer cell lines.Setting: The study was conducted at a tertiary research hospital.Patients: Patients underwent surgical resection for a thyroid tumor from 2000 to 2003 at our institution.Interventions: There were no interventions.Main Outcome Measure: Final surgical pathology diagnosis was the main outcome measure.Results: Thyroid tumors showed hypermethylation for the followingmarkers: Rassf1A, TSHR, RAR-beta 2, DAPK, CDH1, TIMP3, and TGF-beta. A trend toward multiple hypermethylation was evident in cancer tissues, with hypermethylation of two or more markers detectable in 25% of hyperplasias, 38% of adenomas, 48% of thyroid cancers, and 100% of cell lines. A rank correlation analysis of marker hypermethylation suggests that a subset of these markers is epigenetically modified in concert, which may reflect an organ-specific regulation process. Furthermore, a positive correlation was found between the BRAF mutation and RAR-beta 2, and a negative correlation was found between the BRAF mutation and Rassf1A.Conclusions: Methylation-induced gene silencing appears to affect multiple genes in thyroid tissue and increases with cancer progression. Additional markers with better discriminatory power between benign and malignant samples are needed for the diagnostic assessment of cytologically indeterminate thyroid nodules.