title: Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.
abstract: Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.
authors: INSERM, UMR970, Paris-Cardiovascular Research Center, F-75015, Paris, France.
authors: Luis Jaime
authors: LJ
authors: Castro-Vega
authors: Alexandre
authors: A
authors: Buffet
authors: Aguirre A
authors: AA
authors: De Cubas
authors: Alberto
authors: A
authors: Cascón
authors: Mélanie
authors: M
authors: Menara
authors: Emmanuel
authors: E
authors: Khalifa
authors: Laurence
authors: L
authors: Amar
authors: Sharona
authors: S
authors: Azriel
authors: Isabelle
authors: I
authors: Bourdeau
authors: Olivier
authors: O
authors: Chabre
authors: Maria
authors: M
authors: Currás-Freixes
authors: Valérie
authors: V
authors: Franco-Vidal
authors: Marine
authors: M
authors: Guillaud-Bataille
authors: Christophe
authors: C
authors: Simian
authors: Aurélie
authors: A
authors: Morin
authors: Rocío
authors: R
authors: Letón
authors: Alvaro
authors: A
authors: Gómez-Graña
authors: Patrick J
authors: PJ
authors: Pollard
authors: Pierre
authors: P
authors: Rustin
authors: Mercedes
authors: M
authors: Robledo
authors: Judith
authors: J
authors: Favier
authors: Anne-Paule
authors: AP
authors: Gimenez-Roqueplo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005091:Exons / Q000235:genetics; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D055815:Young Adult
chemical_list: D005649:Fumarate Hydratase