title: Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.
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 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.
authors.affiliation: National Cancer Institute-Center for Cancer Research, Bethesda, MD 20892-4265, USA.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.forename: Carly
authors.initials: C
authors.lastname: Smith
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.forename: William I
authors.initials: WI
authors.lastname: Smith
authors.forename: Mona S
authors.initials: MS
authors.lastname: Jahromi
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xekouki
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walker
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.forename: Zengfeng
authors.initials: Z
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Jones
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Waterfall
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: O'Sullivan
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Constantine
authors.initials: C
authors.lastname: Stratakis
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Schiffman
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Lee
authors.initials: L
authors.lastname: Helman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
mesh_terms: D019175:DNA Methylation; D057890:Epigenomics; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006801:Humans; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D013385:Succinate Dehydrogenase
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