Whole-Exome Sequencing Identifies MDH2 as a New Familial Paraganglioma Gene. (12th March 2015)

• Record Type: Journal Article
• Authors: Cascón, 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, Mercedes
• Is Part Of: Journal of the National Cancer Institute. Volume 107:Number 5(2015:May)
• Publication Date: 2015-03-12
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djv053
• Languages: English
• ISSNs: 0027-8874

Abstract

Abstract : 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.