Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene
Alberto Cascón1, Iñaki Comino-Méndez1, María Currás-Freixes1
1: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Spain (AC, ICM, MCF, AAdC, VM, LIP, RL, AGG, MAR, CRA, MR); Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain (AC, LC, LIP, CRA, JS, MU, MR); Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma de Madrid and Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain (LC, JS); Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany (SR, MP, GE); Departments of Pathology (APB) and Endocrinology and Nutrition Service (MC), Hospital 12 de Octubre, Madrid, Spain; Endocrinology Service, Hospital Infanta Sofía, San Sebastián de los Reyes, Spain (SA); Department of Endocrinology and Nutrition Service, Hospital de Fuenlabrada, Madrid, Spain (RVV); Endocrinology Service, Hospital Puerta de Hierro, Majadahonda, Madrid, Spain (JA); Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet, Barcelona, Spain (FS, SM, ME); Department of Pathology, MD Anderson Cancer Center Madrid, Madrid, Spain (JFG); Molecular Cytogenetics Group (ARM), Monoclonal Antibodies Unit, Biotechnology Programme (GR), and Familial Cancer Clinical Unit (MU), Spanish National Cancer Research Centre, Madrid, Spain.
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.
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