RT Journal Article
T1 Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.
A1 Remacha, Laura
A1 Pirman, David
A1 Mahoney, Christopher E
A1 Coloma, Javier
A1 Calsina, Bruna
A1 Curras-Freixes, Maria
A1 Leton, Rocío
A1 Torres-Perez, Rafael
A1 Richter, Susan
A1 Pita, Guillermo
A1 Herraez, Belen
A1 Cianchetta, Giovanni
A1 Honrado, Emiliano
A1 Maestre, Lorena
A1 Urioste, Miguel
A1 Aller, Javier
A1 Garcia-Uriarte, Oscar
A1 Galvez, Maria Angeles
A1 Luque, Raul M
A1 Lahera, Marcos
A1 Moreno-Rengel, Cristina
A1 Eisenhofer, Graeme
A1 Montero-Conde, Cristina
A1 Rodriguez-Antona, Cristina
A1 Llorca, Oscar
A1 Smolen, Gromoslaw A
A1 Robledo, Mercedes
A1 Cascon, Alberto
K1 DLST
K1 TCA cycle
K1 Cancer susceptibility gene
K1 Paraganglioma
K1 Pheochromocytoma
AB Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13C5-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (∼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.
PB Cell Press
YR 2019
FD 2019-02-14
LK http://hdl.handle.net/10668/13773
UL http://hdl.handle.net/10668/13773
LA en
NO Remacha L, Pirman D, Mahoney CE, Coloma J, Calsina B, Currás-Freixes M, et al.  Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. Am J Hum Genet. 2019 Apr 4;104(4):651-664
NO This work was supported by the Instituto de Salud Carlos III (ISCIII), through the ‘‘Accio´n Estrate´gica en Salud’’ (AES) (projects PI15/00783 and PI18/00454 to A.C. and PI17/01796 to M.R.); cofounded by the European Regional Development Fund [ERDF]), and the Deutsche Forschungsgemeinschaft (DFG RI2684/1-1 to S.R.). The Human Genotyping Unit is a member of the Centro Nacional de Genotipado – Plataforma de Recursos Biomoleculares(CeGen-PRB3) and is supported by grant PT17/0019 of the PE IþDþi 2013–2016, funded by ISCIII and ERDF
DS RISalud
RD Apr 7, 2025