Details

Autor(en) / Beteiligte

• Killian, J Keith
• Kim, Su Young
• Miettinen, Markku
• Smith, Carly
• Merino, Maria
• Tsokos, Maria
• Quezado, Martha
• Smith, Jr, William I
• Jahromi, Mona S
• Xekouki, Paraskevi
• Szarek, Eva
• Walker, Robert L
• Lasota, Jerzy
• Raffeld, Mark
• Klotzle, Brandy
• Wang, Zengfeng
• Jones, Laura
• Zhu, Yuelin
• Wang, Yonghong
• Waterfall, Joshua J
• O'Sullivan, Maureen J
• Bibikova, Marina
• Pacak, Karel
• Stratakis, Constantine
• Janeway, Katherine A
• Schiffman, Joshua D
• Fan, Jian-Bing
• Helman, Lee
• Meltzer, Paul S

Titel

Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor

Ist Teil von

• Cancer discovery, 2013-06, Vol.3 (6), p.648-657

Ort / Verlag

United States

Erscheinungsjahr

2013

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.