Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas
Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas
复制标题
DOI：
10.1210/jc.2012-2993
复制
发表时间：
2013-01-01
影响因子：
5.8
通讯作者：
Bertherat, Jerome
中科院分区：
文献类型：
--
作者：
Barreau, Olivia;Assie, Guillaume;Bertherat, Jerome
目的：DNA甲基化是癌症中基因表达沉默的一种机制。有关肾上腺皮质肿瘤的信息有限。IGF2/H19基因异常甲基化在肾上腺皮质癌中很常见。我们的目的是在全基因组水平上描述肾上腺皮质癌中甲基化的特征，并评估其临床意义及其对基因表达的影响。实验设计：利用Infinium人类甲基化27珠芯片(加利福尼亚州圣迭戈Illumina)研究51例肾上腺皮质癌和84例腺瘤启动子区域CpG岛的甲基化模式。采用MRC-Holland(荷兰阿姆斯特丹)甲基化特异性多重连接依赖探针扩增技术对15例癌组织中33个基因的甲基化进行了研究。从先前的研究(HG-U133Plus2.0 AffymetrixGeneChip；Affymetrix，Santa Clara，CA)获得了87个肿瘤的基因表达数据。结果：癌组织的甲基化程度高于腺瘤组织(t检验P=3.1×10(-9))。DNA甲基化图谱的非监督聚类发现了两组癌症，其中一组甲基化水平升高，引发CpG岛甲基化表型(CIMP)。高甲基化的癌进一步分为两个亚组，具有不同程度的甲基化(CIMP-高和CIMP-低)。这种分类可以通过甲基化特异的多重连接依赖的探针扩增来证实。高甲基化与预后不良相关(COX模型P=0.02)。转录组/甲基化相关分析显示1741个基因(12,250个)呈负相关，排名靠前的基因是H19和其他抑癌基因(PLAGL-1，G0S2和NDRG2)。结论：全基因组甲基化分析揭示了肾上腺皮质癌中存在高甲基化，预后较差。这些肿瘤中的高甲基化对于沉默特定的肿瘤抑制基因是重要的。(J Clin Endocrinol Metab 98：E174-E184,2013)
Purpose: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression.Experimental Design: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium Human Methylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors.Results: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 x 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2).Conclusions: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes. (J Clin Endocrinol Metab 98: E174-E184, 2013)