National Cancer Institute-Center for Cancer Research, Bethesda, MD 20892-4265, USA.
Cancer Discov. 2013 Jun;3(6):648-57. doi: 10.1158/2159-8290.CD-13-0092. Epub 2013 Apr 2.
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.
胃肠道间质瘤（GIST）具有信号转导激酶的驱动突变，如 KIT，或者表现为线粒体琥珀酸脱氢酶（SDH）复合物的功能丧失缺陷，SDH 复合物是三羧酸循环和电子传递链的一个组成部分。我们发现 SDH 缺陷型 GIST（n = 24）与 KIT 酪氨酸激酶通路突变型 GIST（n = 39）的 DNA 甲基化谱之间存在显著差异。福尔马林固定石蜡包埋组织的 Infinium 450K 甲基化阵列分析显示，相对于 KIT 突变组（84.9 K 个靶标），SDH 缺陷型 GIST 的基因组超甲基化程度高出一个数量级（84.9 K 个靶标）。在发育上不同的 SDH 缺陷型副神经节瘤/嗜铬细胞瘤（n = 29）中也发现了表观基因组的差异。将 SDH 突变型 GIST 与另一种三羧酸循环缺陷性肿瘤类型异柠檬酸脱氢酶突变型胶质瘤进行比较，发现全基因组低甲基化和高甲基化的程度相当。这些数据揭示了琥珀酸代谢与肿瘤发生过程中基因组 DNA 甲基化之间的重要联系，并普遍表明线粒体三羧酸循环参与核表观基因组的维持。
