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 fixed (FFPE) tissues disclosed an order of magnitude greater genomic hypermethylation from gastric smooth muscle reference in SDH-deficient GIST versus the KIT mutant group (84.9K vs. 8.4K 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 (IDH)-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.
- Received December 12, 2012.
- Accepted April 1, 2013.
- Copyright © 2013, American Association for Cancer Research.