title: SDH mutations establish a hypermethylator phenotype in paraganglioma.
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.
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, 75013 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martinelli
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.forename: Nelly
authors.initials: N
authors.lastname: Burnichon
authors.forename: Nasséra
authors.initials: N
authors.lastname: Abermil
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.forename: Mélanie
authors.initials: M
authors.lastname: Menara
authors.forename: An Thach
authors.initials: AT
authors.lastname: Nguyen
authors.forename: Paule
authors.initials: P
authors.lastname: Benit
authors.forename: Alexandre
authors.initials: A
authors.lastname: Buffet
authors.forename: Charles
authors.initials: C
authors.lastname: Marcaillou
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Aurélien
authors.initials: A
authors.lastname: De Reyniès
authors.forename: Anne-Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002648:Child; D019439:Chromaffin Cells / Q000166:cytology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D059467:Transcriptome
chemical_list: D006657:Histones; D013385:Succinate Dehydrogenase