Abstract 2963: Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.

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Abstract Although driver mutations in signal transduction kinases such as KIT are found in the majority of gastrointestinal stromal tumors (GIST), a subset of GISTs lack these mutations and instead exhibit loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle. To examine the effects of this metabolic defect on the epigenome, we used Illumina GoldenGate and 450K Infinium microarray technology to profile DNA methylation in GIST samples and uncovered markedly divergent global DNA methylation between SDH-null GIST (N=24) versus KIT or related tyrosine kinase pathway mutated GIST (N=39). When compared to reference normal tissues including intestinal smooth muscle (N=10) and neuronal tissue (N=13), SDH-deficient GIST was found to have an order of magnitude greater global hypermethylation than the kinase-pathway mutant group (84.9K vs. 8.4K targets, respectively). In a histologically distinct SDH-deficient tumor system, methylation divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (N=29) using an adrenal tissue (N=15) reference baseline. These data expose an essential role for succinate metabolism in the maintenance of DNA methylation programming and tumor suppression. Because defects in other Krebs cycle enzymes are also oncogenic, we further sought to determine whether this phenomenon was confined to SDH-deficient tumors. Analysis of SDH-mutant GIST and isocitrate dehydrogenase (IDH)-mutant gliomas revealed comparable quantities of global hypo- and hypermethylated targets. We propose that this phenomenon may result from a failure of maintenance demethylation, secondary to inactivation of the TET2 5-methylcytosine dioxgenase system by the inhibitory metabolites succinate (in SDH deficient tumors) or 2-hydroxyglutarate (in IDH mutant tumors). While the biological ramifications of this distortion of the epigenome remain to be elucidated, this study clearly implicates the Krebs cycle as mitochondrial custodian of the methylome in diverse cancers. Citation Format: Paul S. Meltzer, J. Keith Killian, Su Young Kim, Markku Miettinen, Carly Smith, Maria Tsokos, Martha Quezado, William I. Smith, Mona S. Jahromi, Robert L. Walker, Jerzy Lasota, Brandy Klotzle, Zengfeng Wang, Laura Jones, Yuelin Zhu, Yonghong Wang, Joshua J. Waterfall, Marina Bibikova, Maureen J. O'Sullivan, Constantine A. Stratakis, Joshua D. Schiffman, Jian-Bing Fan, Lee Helman. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2013-2963