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Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor

2013; American Association for Cancer Research; Volume: 3; Issue: 6 Linguagem: Inglês

10.1158/2159-8290.cd-13-0092

2159-8290

Jonathan Keith Killian, Su Young Kim, Markku Miettinen, Carly Smith, Maria J. Merino, Maria Tsokos, Martha Quezado, William I. Smith, Mona S. Jahromi, Paraskevi Xekouki, Eva Szarek, Robert L. Walker, Jerzy Lasota, Mark Raffeld, Brandy Klotzle, Zengfeng Wang, Laura Jones, Yuelin J. Zhu, Yonghong Wang, Joshua J. Waterfall, Maureen J. O’Sullivan, Marina Bibikova, Karel Pacák, Constantine A. Stratakis, Katherine A. Janeway, Joshua D. Schiffman, Jian-Bing Fan, Lee J. Helman, Paul S. Meltzer,

Cancer, Hypoxia, and Metabolism

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.