Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas:: Association to malignant behavior
Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas:: Association to malignant behavior
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DOI：
10.1158/1078-0432.ccr-07-1867
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发表时间：
2008-05-01
影响因子：
11.5
通讯作者：
Larsson, Catharina
中科院分区：
文献类型：
--
作者：
Geli, Janos;Kiss, Nimrod;Larsson, Catharina
目的：本研究旨在定量评估嗜铬细胞瘤和腹部副神经节瘤的启动子和整体甲基化变化及其与肿瘤表型的关系。实验设计：通过定量亚硫酸氢盐焦磷酸测序对 53 个原发性肿瘤（42 个良性，11 个恶性）进行分析。根据肿瘤抑制基因 p16(INK4A)、CDH1、DCR2、RARB、RASSF1A、NOREM、TP73、APC、DAPK1、p14(ARF) 和 PTEN 的甲基化水平，CpG 岛甲基化表型 (CIMP) 被定义为三个或更多基因中的协同高甲基化。计算超甲基化启动子的平均 Z 分数以表征总体启动子甲基化。通过发光甲基化分析对 LINE-1 启动子序列的整体 DNA 甲基化进行定量。结果：5 个原发性肿瘤 (9.4%) 表现出 CIMP 表型，其中 4 个是恶性副神经节瘤。 CIMP 与恶性行为 (P = 0.005) 和就诊年龄较轻 (P < 0.007) 显着相关，但并非由 BRAF V600E 突变引起。与正常肾上腺样本相比，在肿瘤中观察到 LINE-1 元件的整体低甲基化（P < 0.02）。结论：我们在此描述了腹部副神经节瘤中 CIMP 的鉴定，以及该表型与恶性行为以及就诊年龄的紧密相关性。这些发现为表观遗传作用药物对预后不良的年轻腹部副神经节瘤患者亚组的潜在益处提供了前景。
Purpose: This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes.Experimental Design: A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16(INK4A), CDH1, DCR2, RARB, RASSF1A, NOREM, TP73, APC, DAPK1, p14(ARF) and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis.Results: Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02).Conclusion: We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation, The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.