Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor

J. Keith Killian, Su Young Kim, Markku Miettinen, Carly Smith, Maria 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 Zhu, Yonghong Wang, Joshua J. WaterfallMaureen J. O'Sullivan, Marina Bibikova, Karel Pacak, Constantine Stratakis, Katherine A. Janeway, Joshua D. Schiffman, Jian Bing Fan, Lee Helman, Paul S. Meltzer

Research output: Contribution to journalArticlepeer-review

Abstract

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 hypoand 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. SIGNIFICANCE: 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.

Original languageEnglish (US)
Pages (from-to)648-657
Number of pages10
JournalCancer discovery
Volume3
Issue number6
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Oncology

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