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

• Published in: JNCI : Journal of the National Cancer Institute Vol. 107; no. 5; p. 1
• Main 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
• Format: Journal Article
• Language: English
• Published: United States Oxford Publishing Limited (England) 01.05.2015
• Subjects: Cancer; Citric Acid Cycle; Deoxyribonucleic acid; DNA; DNA, Neoplasm - analysis; Down-Regulation; Enzymes; Exome; Fumarates - metabolism; Gene expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Germ-Line Mutation; HeLa Cells; Humans; Malate Dehydrogenase - genetics; Malate Dehydrogenase - metabolism; Malates - metabolism; Male; Middle Aged; Mutation; Paraganglioma - genetics; Paraganglioma - metabolism; Pheochromocytoma - genetics; Pheochromocytoma - metabolism; Sequence Analysis, DNA; Tumors
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djv053

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.