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oai:repisalud.isciii.es:20.500.12105/260542025-12-18T12:55:56Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Cascon Soriano, Alberto author Comino-Méndez, Iñaki author Currás-Freixes, María author de Cubas, Aguirre A author Contreras, Laura author Richter, Susan author Peitzsch, Mirko author Mancikova, Veronika author Inglada-Pérez, Lucía author Pérez-Barrios, Andrés author Calatayud, María author Azriel, Sharona author Villar-Vicente, Rosa author Aller, Javier author Setién, Fernando author Moran, Sebastian author Garcia, Juan F author Río-Machín, Ana author Letón, Rocío author Gómez-Graña, Álvaro author Apellániz-Ruiz, María author Roncador, Giovanna author Esteller, Manel author Rodríguez-Antona, Cristina author Satrústegui, Jorgina author Eisenhofer, Graeme author Urioste, Miguel author Robledo Batanero, Mercedes author 2015-03-11 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. J Natl Cancer Inst . 2015 Mar 11;107(5):djv053 J Natl Cancer Inst 25766404 https://hdl.handle.net/20.500.12105/26054 SUCCINATE-DEHYDROGENASE MUTATIONS PHEOCHROMOCYTOMA SDHB FUMARATE CANCER Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene.