Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which enco...

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Detalles Bibliográficos
Autores: Cascon Soriano, Alberto, Comino-Méndez, Iñaki, Currás-Freixes, María, de Cubas, Aguirre A, Contreras, Laura, Richter, Susan, Peitzsch, Mirko, Mancikova, Veronika, Inglada-Pérez, Lucía, Pérez-Barrios, Andrés, Calatayud, María, Azriel, Sharona, Villar-Vicente, Rosa, Aller, Javier, Setién, Fernando, Moran, Sebastian, Garcia, Juan F, Río-Machín, Ana, Letón, Rocío, Gómez-Graña, Álvaro, Apellániz-Ruiz, María, Roncador, Giovanna, Esteller, Manel, Rodríguez-Antona, Cristina, Satrústegui, Jorgina, Eisenhofer, Graeme, Urioste, Miguel, Robledo Batanero, Mercedes
Tipo de recurso: artículo
Fecha de publicación:2015
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26054
Acceso en línea:https://hdl.handle.net/20.500.12105/26054
Access Level:acceso abierto
Palabra clave:SUCCINATE-DEHYDROGENASE
MUTATIONS
PHEOCHROMOCYTOMA
SDHB
FUMARATE
CANCER
Descripción
Sumario:Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six- and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P = .043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P = .033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene.

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