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Cancer Cell. 2013 Jun 10;23(6):739-52. doi: 10.1016/j.ccr.2013.04.018. Epub 2013 May 23.

SDH mutations establish a hypermethylator phenotype in paraganglioma.

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1
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.

Abstract

Paragangliomas are neuroendocrine tumors frequently associated with mutations in RET, NF1, VHL, and succinate dehydrogenase (SDHx) genes. Methylome analysis of a large paraganglioma cohort identified three stable clusters, associated with distinct clinical features and mutational status. SDHx-related tumors displayed a hypermethylator phenotype, associated with downregulation of key genes involved in neuroendocrine differentiation. Succinate accumulation in SDH-deficient mouse chromaffin cells led to DNA hypermethylation by inhibition of 2-OG-dependent histone and DNA demethylases and established a migratory phenotype reversed by decitabine treatment. Epigenetic silencing was particularly severe in SDHB-mutated tumors, potentially explaining their malignancy. Finally, inactivating FH mutations were identified in the only hypermethylated tumor without SDHx mutations. These findings emphasize the interplay between the Krebs cycle, epigenomic changes, and cancer.

PMID:
23707781
DOI:
10.1016/j.ccr.2013.04.018
[Indexed for MEDLINE]
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