A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer
A genome-wide search identifies epigenetic silencing of somatostatin, tachykinin-1, and 5 other genes in colon cancer
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DOI：
10.1053/j.gastro.2006.06.006
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发表时间：
2006-09-01
期刊：
影响因子：
29.4
通讯作者：
Meltzer, Stephen J.
中科院分区：
文献类型：
--
作者：
Mori, Yuriko;Cai, Kun;Meltzer, Stephen J.
背景与目的：通过启动子高甲基化导致的基因沉默是癌症发病机制中的一个中心事件。为了鉴定结肠癌中的新甲基化靶点，我们进行了全基因组、基于微阵列、计算机模拟和表观遗传学搜索。研究方法：首先进行互补DNA微阵列实验以鉴定在原发性结肠癌中下调的基因和在通过5-氮杂-2 '-脱氧胞苷进行整体DNA去甲基化后在结肠癌细胞系中上调的基因。然后通过将这些微阵列数据与计算机遗传学和功能搜索相结合来鉴定候选甲基化靶标。通过这些搜索识别的候选基因进一步研究了结肠癌中使用甲基化特异性聚合酶链反应的启动子超甲基化。结果：我们鉴定了51个新的和3个已知的候选甲基化靶点。随后的表观遗传学分析显示，原发性结肠癌表现出频繁的甲基化生长抑素（SST，30 34例，88%）和P物质前体基因速激肽-1（TACI; 16 34例，47%）。Dukes A/B组TACI甲基化强度显著高于Dukes C/D组（P = 0.01）。低水平微卫星不稳定性（MSI-L）的SST甲基化强度显著高于非MSI-L癌症（P = 0.02）。甲基化与SST和TACI的信使RNA下调相关。此外，我们还分离出了新的启动子甲基化靶点：NELL 1、AKAP 12、caveolin-1、endoglin和MAL. Conclusions：这些数据强烈表明SST和TAC 1参与了结肠癌的发生。现在需要进一步的研究来阐明它们参与结肠癌的机制及其作为临床生物标志物的价值。NELL 1、AKAP 12、caveolin-1、endoglin和MAL也是值得进一步研究的有希望的肿瘤抑制基因候选者。
Background & Aims: Gene silencing via promoter hypermethylation is a central event in the pathogenesis of cancers. To identify novel methylation targets in colon cancer, we conducted a genome-wide, microarray-based, in silico, and epigenetic search. Methods: Complementary DNA microarray experiments were first performed to identify genes down-regulated in primary colon cancers and up-regulated in colon cancer cell lines after global DNA demethylation by 5-aza-2'-deoxycitidine. Candidate methylation targets were then identified by combining these microarray data with in silico genetic and functional searches. Candidate genes recognized by these searches were further investigated for promoter hypermethylation in colon cancer using methylation-specific polymerase chain reaction. Results: We identified 51 novel and 3 known candidate methylation targets. Subsequent epigenetic analysis revealed that primary colon cancers demonstrated frequent methylation of somatostatin (SST, 30 of 34 cases, 88%) and the substance P precursor gene tachykinin-1 (TACI; 16 of 34 cases, 47%). TACI methylation intensity was significantly higher in Dukes A/B than in Dukes C/D cancers (P = .01). SST methylation intensity was significantly higher in low-level microsatellite instability (MSI-L) than in non-MSI-L cancers (P = .02). Methylation was associated with messenger RNA down-regulation for both SST and TACI. Furthermore, we isolated S additional novel promoter methylation targets: NELL1, AKAP12, caveolin-1, endoglin, and MAL. Conclusions: These data strongly suggest that SST and TAC1 are involved in colon carcinogenesis. Further studies are now indicated to elucidate mechanisms underlying their involvement in colon cancer and their values as clinical biomarkers. NELL1, AKAP12, caveolin-1, endoglin, and MAL are also promising tumor suppressor gene candidates deserving of further study.