Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Illumina GoldenGate Methylation Cancer Panel I: Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array. Illumina HumanMethylation450 BeadChip: Bisulfite-converted gDNAs from 76 samples were analyzed with the Illumina 450K Infinium Methylation assay.