Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.
Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.
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DOI：
10.1158/2159-8290.cd-13-0092
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发表时间：
2013-06
期刊：
影响因子：
28.2
通讯作者：
Meltzer PS
中科院分区：
文献类型：
--
作者：
Killian JK;Kim SY;Miettinen M;Smith C;Merino M;Tsokos M;Quezado M;Smith WI Jr;Jahromi MS;Xekouki P;Szarek E;Walker RL;Lasota J;Raffeld M;Klotzle B;Wang Z;Jones L;Zhu Y;Wang Y;Waterfall JJ;O'Sullivan MJ;Bibikova M;Pacak K;Stratakis C;Janeway KA;Schiffman JD;Fan JB;Helman L;Meltzer PS
胃肠道间质瘤(GIST)含有KIT等信号转导激酶的驱动突变，或者表现为线粒体琥珀酸脱氢酶(SDH)复合体功能缺失，SDH是Krebs循环和电子传输链的组成部分。我们发现SDH缺陷型GIST(n=24)和KIT酪氨酸激酶途径突变的GIST(n=39)的DNA甲基化特征有显著差异。对福尔马林固定的石蜡包埋组织进行的Infinium450K甲基化阵列分析显示，相对于SDH缺陷的GIST组，基因组超甲基化程度比KIT-突变组高出一个数量级(84.9K比8.4K靶标)。在SDH突变的副神经节瘤/嗜铬细胞瘤(n=29)中，进一步发现了表观基因组的差异，这是一种发育不同的SDH缺乏的肿瘤系统。SDH突变的GIST与异柠檬酸脱氢酶突变的胶质瘤(另一种Krebs周期缺陷肿瘤类型)的比较，揭示了全球低甲基化和高甲基化的类似措施。这些数据揭示了肿瘤发生过程中琥珀酸代谢和基因组DNA甲基化之间的重要联系，并通常涉及核表观基因组维持中的线粒体Krebs循环。这项研究表明，SDH缺乏是多种肿瘤谱系普遍存在的DNA高甲基化的基础，通常将Krebs周期定义为线粒体对甲基组的保管人。我们认为，这种现象可能是由于抑制了Tet 5-甲基胞嘧啶二加氧酶去甲基化途径，继而导致维持CpG去甲基化的失败，是由于肿瘤中积累了Krebs循环功能障碍的抑制性代谢产物所致。
Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway–mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH -mutant GIST with isocitrate dehydrogenase -mutant glioma, another Krebs cycle–defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance. This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction.