Divergence in Gastrointestinal Stromal Tumor Succinate Dehydrogenase Mutation Underlies Global Epigenomic

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 profi les of SDH-defi cient GIST ( n = 24) versus KIT tyrosine kinase pathway–mutated GIST ( n = 39). Infi nium 450K methylation array analysis of formalin-fi xed paraffi n-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-defi cient 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-defi cient 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 defi ciency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defi ning 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. Cancer Discov; 3(6); 648–57. ©2013 AACR. Authors’ Affi liations: 1 National Cancer Institute-Center for Cancer Research; 2 Suburban Hospital; 3 Eunice Kennedy Shriver NICHD, Bethesda, Maryland; 4 University of Utah, Salt Lake City, Utah; 5 Illumina, Inc., San Diego, California; 6 Dana Farber Cancer Institute, Boston, Massachusetts; 7 Our Lady’s Children’s Hospital, Dublin, Ireland Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Paul S. Meltzer, Genetics Branch, National Cancer Institute, 37 Convent Drive MSC 4265, Bethesda, MD 20892-4265. Phone: 301-496-5266; Fax: 301-402-3241; E-mail: [email protected] doi: 10.1158/2159-8290.CD-13-0092 ©2013 American Association for Cancer Research. on May 27, 2014. © 2013 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst April 2, 2013; DOI: 10.1158/2159-8290.CD-13-0092