SDH mutations establish a hypermethylator phenotype in paraganglioma

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Cell Movement / genetics
  • Child
  • Chromaffin Cells / cytology
  • Chromaffin Cells / metabolism
  • Colorectal Neoplasms / genetics
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Gene Knockout Techniques
  • Gene Silencing
  • Glioblastoma / genetics
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Paraganglioma / genetics
  • Paraganglioma / pathology*
  • Phenotype
  • Pheochromocytoma / genetics
  • Pheochromocytoma / pathology
  • Succinate Dehydrogenase / genetics*
  • Succinate Dehydrogenase / metabolism
  • Succinate Dehydrogenase / physiology
  • Transcriptome

Substances

  • Histones
  • Succinate Dehydrogenase

Associated data

  • GEO/GSE43298