Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.
نویسندگان
چکیده
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.
منابع مشابه
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) versu...
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متن کاملAuthor's response to reviews Title: SDHA Loss of Function Mutations in a Subset of Young Adult Wild-type Gastrointestinal Stromal Tumors Authors: ANTOINE ITALIANO ([email protected])
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ورودعنوان ژورنال:
- Cancer discovery
دوره 3 6 شماره
صفحات -
تاریخ انتشار 2013