Cascon Soriano, AlbertoComino-Méndez, IñakiCurrás-Freixes, Maríade Cubas, Aguirre AContreras, LauraRichter, SusanPeitzsch, MirkoMancikova, VeronikaInglada-Pérez, LucíaPérez-Barrios, AndrésCalatayud, MaríaAzriel, SharonaVillar-Vicente, RosaAller, JavierSetién, FernandoMoran, SebastianGarcia, Juan FRío-Machín, AnaLetón, RocíoGómez-Graña, ÁlvaroApellániz-Ruiz, MaríaRoncador, GiovannaEsteller, ManelRodríguez-Antona, CristinaSatrústegui, JorginaEisenhofer, GraemeUrioste, MiguelRobledo Batanero, Mercedes2025-01-172025-01-172015-03-11J Natl Cancer Inst . 2015 Mar 11;107(5):djv053https://hdl.handle.net/20.500.12105/26054Disruption 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.This work was supported in part by the Fondo de Investigaciones Sanitarias (grants PI12/00236 and PI11/01359 to AC and MR, respectively), FP7 grant HEALTH-F2-2010-259735 (ENS@T-CANCER). SR and GE were supported by the Deutsche Forschungsgemeinschaft EI855/1/1.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/SUCCINATE-DEHYDROGENASEMUTATIONSPHEOCHROMOCYTOMASDHBFUMARATECANCERAttribution-NonCommercial-NoDerivatives 4.0 International257664041075djv053J Natl Cancer Instopen access