Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations.
The tricarboxylic acid, or Krebs, cycle is central to the cellular metabolism of sugars, lipids, and amino acids; it fuels the mitochondrial respiratory chain for energy generation. In the past decade, mutations in the Krebs-cycle enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase have been documented to be causally involved in carcinogenesis. This review is focused on the relationship between SDH mutations and the carcinogenic phenotype. The succinate dehydrogenase complex catalyzes the oxidation of succinate to fumarate; mutations in its subunits SDHA, SDHB, SDHC, and SDHD, and in the assembly factor SDHAF2, result in syndromes with distinct tumor types, including pheochromocytoma/paraganglioma, gastrointestinal stromal tumor, and, less often, renal-cell carcinoma and pituitary adenoma. In this study we collected all previously reported SDH mutations with the aim of defining their nature and tumor spectrum. In addition, genotype-phenotype correlations as well as mechanisms of biallelic inactivation were analyzed in the SDH-deficient setting. Finally, we performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor to predict the functional impact of nonsynonymous mutations. The prediction of the latter was further compared with available SDHA and/or SDHB immunohistochemistry data.
1] Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium [2] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands [3] Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Lucie
L
Evenepoel
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
Thomas G
TG
Papathomas
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
Niels
N
Krol
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
Esther
E
Korpershoek
1] Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands [2] Department of Pathology, Reinier de Graaf Hospital, Delft, The Netherlands.
Ronald R
RR
de Krijger
Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
Alexandre
A
Persu
Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.
Winand N M
WN
Dinjens
D000818:Animals; D018095:Germ-Line Mutation; D006801:Humans; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*
D013385:Succinate Dehydrogenase