Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor
- PMID: 23550148
- PMCID: PMC4135374
- DOI: 10.1158/2159-8290.CD-13-0092
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.
Conflict of interest statement
B. Klotzle and M. Bibikova are employees of Illumina, Inc. J.D. Schiffman is a consultant/advisory board member of Affymetrix, Inc. J.-B. Fan is an employee of Illumina, Inc. No potential conflicts of interest were disclosed by the other authors.
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Comment in
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Metabolism: Epigenetic links to the web of Krebs.Nat Rev Cancer. 2013 Jul;13(7):437. doi: 10.1038/nrc3551. Epub 2013 Jun 20. Nat Rev Cancer. 2013. PMID: 23783118 No abstract available.
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