Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Gut. 2012 Mar;61(3):392-401. doi: 10.1136/gut.2011.241034. Epub 2011 Jun 27.
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.
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).
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).
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.
大多数胃肠道间质瘤（GIST）存在 KIT 突变；然而，可能增强 GIST 侵袭性的表观遗传异常在很大程度上尚未被确定。我们的目的是建立与 GIST 恶性转化相关的表观遗传谱。
分析了四个肿瘤抑制基因 RASSF1A、p16、CDH1 和 MGMT 的甲基化情况。此外，在一个训练集（n=40）中，使用甲基化 GpG 岛扩增微阵列（MCAM）比较了小、恶性倾向和恶性 GIST 之间的全基因组 DNA 甲基化谱。在验证集（n=75）中，测试了 MCAM 鉴定的基因甲基化状态与疾病临床特征之间的关系。
RASSF1A 的甲基化从小 GIST 逐渐增加到恶性 GIST。p16 仅在恶性倾向和恶性 GIST 中被甲基化。MCAM 分析表明，晚期 GIST 中甲基化的基因多于小 GIST（分别为平均 473 个基因和 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 REC8 和 PAX3 在训练和验证集中的小 GIST 和恶性 GIST 中存在差异甲基化。至少有 REC8、PAX3 或 p16 甲基化的患者预后明显较差（P=0.034）。
我们的结果表明，从表观遗传学角度来看，GIST 不是一种单一的疾病，一组基因的 DNA 甲基化与侵袭性临床行为和不良预后相关。鉴定出的基因可能潜在地作为预测生存能力差的侵袭性 GIST 的生物标志物。
