Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

ABSTRACT: 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. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.

ORGANISM(S): Homo sapiens

SUBMITTER: Jack Zhu

PROVIDER: E-GEOD-34387 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.

Killian J Keith JK Kim Su Young SY Miettinen Markku M Smith Carly C Merino Maria M Tsokos Maria M Quezado Martha M Smith William I WI Jahromi Mona S MS Xekouki Paraskevi P Szarek Eva E Walker Robert L RL Lasota Jerzy J Raffeld Mark M Klotzle Brandy B Wang Zengfeng Z Jones Laura L Zhu Yuelin Y Wang Yonghong Y Waterfall Joshua J JJ O'Sullivan Maureen J MJ Bibikova Marina M Pacak Karel K Stratakis Constantine C Janeway Katherine A KA Schiffman Joshua D JD Fan Jian-Bing JB Helman Lee L Meltzer Paul S PS

Cancer discovery 20130402 6

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- ...[more]

PMID: 23550148

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Project description:Introduction: Five different molecular subtypes of breast cancer have been identified through gene expression profiling. Each subtype has a characteristic expression pattern suggested to partly depend on cellular origin. We aimed to investigate whether the molecular subtypes also display distinct methylation profiles. Methods: We analysed methylation status of 807 cancer-related genes in 189 fresh frozen primary breast tumours and four normal breast tissue samples using an array-based methylation assay. Results: Unsupervised analysis revealed three groups of breast cancer with characteristic methylation patterns. The three groups were associated with the luminal A, luminal B and basal-like molecular subtypes of breast cancer, respectively, whereas cancers of the HER2-enriched and normal-like subtypes were distributed among the three groups. The methylation frequencies were significantly different between subtypes, with luminal B and basal-like tumours being most and least frequently methylated, respectively. Moreover, targets of the polycomb repressor complex in breast cancer and embryonic stem cells were more methylated in luminal B tumours than in other tumours. BRCA2-mutated tumours had a particularly high degree of methylation. Finally, by utilizing gene expression data, we observed that a large fraction of genes reported as having subtype-specific expression patterns might be regulated through methylation. Conclusions: We have found that breast cancers of the basal-like, luminal A and luminal B molecular subtypes harbour specific methylation profiles. Our results suggest that methylation may play an important role in the development of breast cancers. DNA methylation profiling of breast cancer samples and normal breast tissue samples. The Illumina GoldenGate Methylation Cancer Panel I was used to obtain DNA methylation profiles across approximately 1500 CpGs. Samples included 189 breast cancer samples and 4 normal breast tissue samples. Bisulphite converted DNA from the samples were hybridised to the Illumina GoldenGate Methylation Cancer Panel I

Dataset Information

Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

Publications

Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor.

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