Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene
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Contributors
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.
Details
Original language | English |
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Journal | Journal of the National Cancer Institute |
Volume | 107 |
Issue number | 5 |
Publication status | Published - 1 May 2015 |
Peer-reviewed | Yes |
External IDs
PubMed | 25766404 |
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ORCID | /0000-0002-3549-2477/work/142244888 |