SDH Mutations Establish a Hypermethylator Phenotype in Paraganglioma
Menée sur des échantillons tumoraux prélevés sur 145 patients atteints d'un paragangliome, cette étude française met en évidence le rôle joué par des mutations du gène SDH dans l'hyperméthylation de gènes impliqués dans la différenciation neuroendocrine
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. "SDH and FH mutations establish a hypermethylator phenotype in PGL/PCC "Succinate inhibits DNA and histone demethylases in SDH-deficient chromaffin cells "DNA hypermethylation silences key genes involved in neuroendocrine differentiation "A stronger hypermethylator phenotype may explain malignancy of SDHB-mutated tumors