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: J Keith Killian, Su Young Kim, Markku Miettinen, Carly Smith, Maria Merino, Maria Tsokos, Martha Quezado, William I Smith Jr, 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 Waterfall, Maureen J O'Sullivan, Marina Bibikova, Karel Pacak, Constantine Stratakis, Katherine A Janeway, Joshua D Schiffman, Jian-Bing Fan, Lee Helman, Paul S Meltzer
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 6 Pg. 648-57 (Jun 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23550148 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Succinate Dehydrogenase

Topics

• DNA Methylation
• Epigenomics
• Gastrointestinal Stromal Tumors (enzymology, genetics, pathology)
• Gene Expression Regulation, Neoplastic
• Genomic Instability
• Germ-Line Mutation
• Humans
• Signal Transduction
• Succinate Dehydrogenase (genetics)