Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor
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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. Significance: This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction. Cancer Discov; 3(6); 648–57. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 591
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An increased ratio of succinate to α-KG in cancers resulting from impaired SDH activity is related to pervasive DNA hypermethylation, which contributes to downregulation of key genes implicated in cell differentiation and cancer stages.
“An increased ratio of succinate to α-KG in cancers resulting from impaired succinate dehydrogenase (SDH) activity is related to pervasive DNA hypermethylation, which contributes to the downregulation of key genes implicated in cell differentiation and cancer stages102.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [102]
Tumors with SDH and FH loss share phenotypic features consistent with dioxygenase inhibition, including global increase in DNA methylation and elevated HIF1α.
“Tumors that exhibit SDH- and FH loss share a number of phenotypic features that are consistent with dioxygenase inhibition, among which is a characteristic global increase in DNA methylation (Killian et al., 2013; Letouze et al., 2013; Xiao et al., 2012), as well as elevated levels of HIF1α (Selak et al., 2005).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Killian et al., 2013
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- Authors
- Killian, J. K., Kim, S. Y., Miettinen, M., Smith, C., Merino, M., Tsokos, M., Quezado, M., Smith, W. I., Jahromi, M. S., Xekouki, P., Szarek, E., Walker, R. L., Lasota, J., Raffeld, M., Klotzle, B., Wang, Z., Jones, L., Zhu, Y., Wang, Y., Waterfall, J. J., O'Sullivan, M. J., Bibikova, M., Pacak, K., Stratakis, C., Janeway, K. A., Schiffman, J. D., Fan, J.-B., Helman, L., & Meltzer, P. S.
- Affiliations
- Illumina (United States) (US)
- Authors' Affiliations: 1National Cancer Institute-Center for Cancer Research; 2Suburban Hospital; 3Eunice Kennedy Shriver NICHD, Bethesda, Maryland; 4University of Utah, Salt Lake City, Utah; 5Illumina, Inc., San Diego, California; 6Dana Farber Cancer Institute, Boston, Massachusetts; 7Our Lady's Children's Hospital, Dublin, Ireland
- Corresponding author
- Meltzer, Paul S.
- ORCID
- Killian, J. Keith
- Kim, Su Young
- Miettinen, Markku
- Merino, Maria
- Tsokos, Maria
- Quezado, Martha
- Jahromi, Mona S.
- Xekouki, Paraskevi
- Walker, Robert L.
- Lasota, Jerzy
- Raffeld, Mark
- Wang, Zengfeng
- Jones, Laura
- Zhu, Yuelin
- Wang, Yonghong
- Waterfall, Joshua J.
- Stratakis, Constantine
- Janeway, Katherine A.
- Schiffman, Joshua D.
- Fan, Jian-Bing
- Helman, Lee
- Meltzer, Paul S.
- Venue
- Cancer Discovery
- Published
- 2013-06-01
- Volume
- 3
- Issue
- 6
- Pages
- 648-657
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4135374
- OpenAlex
- W2139631829
- Cited by
- 356
- References
- 26
- Citations by year
- 2026: 20 · 2025: 14 · 2024: 22 · 2023: 26 · 2022: 23 · 2021: 19 · 2020: 24 · 2019: 30 · 2018: 21 · 2017: 27 · 2016: 29 · 2015: 45 · 2014: 41 · 2013: 13 · 2012: 2
- FWCI
- 19.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Cancer Discovery (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD000642)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal Tumor Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- succinate dehydrogenase, gastrointestinal stromal tumor, DNA methylation, KIT mutations, succinate metabolism, paraganglioma, pheochromocytoma, IDH mutation, glioma, cancer metabolism
- MeSH terms
- Humans, Succinate Dehydrogenase, Signal Transduction, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, DNA Methylation, Genomic Instability, Gastrointestinal Stromal Tumors, Epigenomics
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