Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
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DOI：
10.1136/gut.2011.241034
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发表时间：
2012-03-01
期刊：
影响因子：
24.5
通讯作者：
Kondo, Yutaka
中科院分区：
文献类型：
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作者：
Okamoto, Yasuyuki;Sawaki, Akira;Kondo, Yutaka
背景和目的大多数胃肠道间质瘤（GIST）具有KIT突变;然而，可以想象的增强GIST侵袭性的表观遗传异常在很大程度上尚未确定。我们的目的是建立与GISTs恶性转化相关的表观遗传学谱。方法分析GISTs中RASSF 1A、p16、CDH 1和MGMT四个抑癌基因的甲基化。此外，使用甲基化GpG岛扩增微阵列（MCAM）在训练集（n=40）中比较了小的、恶性倾向的和恶性GIST之间的全基因组DNA甲基化谱。结果RASSF 1A基因甲基化水平从小到恶性GIST逐渐增高，随着GIST的发展，RASSF 1A基因甲基化水平逐渐增高，随着GIST的发展，RASSF 1A基因甲基化水平逐渐增高。p16在恶性倾向和恶性GIST中特异性甲基化。MCAM分析显示，晚期GIST中甲基化的基因多于小GIST（平均473个基因vs 360个基因，P=0.012）。有趣的是，恶性GIST的甲基化谱受其位置的显著影响。通过MCAM分析新鉴定的两个基因REC 8和PAX 3在训练集和验证集中的小型和恶性GIST中差异甲基化。REC 8、PAX 3或p16基因甲基化的患者预后明显较差（P= 0.034.Conclusion我们的研究结果表明，GIST在表观遗传学方面不是一种统一的疾病，一组基因的DNA甲基化与侵袭性临床行为和不良预后相关。所确定的基因可能作为预测生存能力差的侵袭性GIST的生物标志物。
Background and aims The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs.Methods Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75).Results Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034).Conclusion Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.