Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas.
Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas.
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DOI：
10.1530/erc-12-0251
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发表时间：
2012-12-01
影响因子：
3.9
通讯作者：
Farrell, William E
中科院分区：
文献类型：
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作者：
Duong, Cuong V;Emes, Richard D;Farrell, William E
DNA甲基化是几种表观遗传修饰之一，与遗传异常一起是肿瘤发生的标志，包括来自脑下垂体的那些。在这项研究中，我们检测了主要垂体腺瘤亚型中27个 578cpG位点的DNA甲基化，这些位点跨越14个 000多个基因。全基因组的变化首先在一个发现的队列中被确定，该队列包括无功能(NF)、生长激素(GH)、催乳素(PRL)分泌和促肾上腺皮质激素(CT)腺瘤相对于死后脑垂体瘤。使用严格的截止标准，我们通过焦磷酸测序验证了16个基因中的12个(75%)的甲基化增加。总体而言，这些标准确定了40个基因在神经纤维组，21个在生长激素组，6个在PRL组，2个在CT组，这些基因与对照组相比存在差异甲基化。在一个较大的独立的腺瘤队列中，对于高甲基化已被证实的基因，存在不同的高甲基化频率，其中13个NF腺瘤中有12个KIAA1822(HIPL1)和TFAP2E基因高甲基化，而在13个腺瘤中有2个COL1A2基因高甲基化。对于显示不同腺瘤亚型间差异甲基化的基因，焦磷酸测序证实了这些发现。在所研究的12个基因中，有3个基因的甲基化与转录表达呈负相关，其中EML2、Rhod和HOXB1的甲基化增加与转录表达显著降低相关。这项研究提供了第一次对腺瘤的全基因组调查，亚型特定的表观基因组变化，并将被证明有助于识别可能预测或表征生长模式的生物标记物。识别基因的功能特征也将提供对肿瘤病因学的洞察和新治疗靶点的识别。
DNA methylation is one of the several epigenetic modifications that together with genetic aberrations are hallmarks of tumorigenesis including those emanating from the pituitary gland. In this study, we examined DNA methylation across 27 578 CpG sites spanning more than 14 000 genes in the major pituitary adenoma subtypes. Genome-wide changes were first determined in a discovery cohort comprising non-functioning (NF), growth hormone (GH), prolactin (PRL)-secreting and corticotroph (CT) adenoma relative to post-mortem pituitaries. Using stringent cut-off criteria, we validated increased methylation by pyrosequencing in 12 of 16 (75%) genes. Overall, these criteria identified 40 genes in NF, 21 in GH, six in PRL and two in CT that were differentially methylated relative to controls. In a larger independent cohort of adenomas, for genes in which hypermethylation had been validated, different frequencies of hypermethylation were apparent, where the KIAA1822 (HHIPL1) and TFAP2E genes were hypermethylated in 12 of 13 NF adenomas whereas the COL1A2 gene showed an increase in two of 13 adenomas. For genes showing differential methylation across and between adenoma subtypes, pyrosequencing confirmed these findings. In three of 12 genes investigated, an inverse relationship between methylation and transcript expression was observed where increased methylation of EML2, RHOD and HOXB1 is associated with significantly reduced transcript expression. This study provides the first genome-wide survey of adenoma, subtype-specific epigenomic changes and will prove useful for identification of biomarkers that perhaps predict or characterise growth patterns. The functional characterisation of identified genes will also provide insight of tumour aetiology and identification of new therapeutic targets.