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oai:repisalud.isciii.es:20.500.12105/230842024-11-29T11:16:16Zcom_20.500.12105_2173com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19597col_20.500.12105_16982

00925njm 22002777a 4500 dc Remacha, Laura author Pirman, David author Mahoney, Christopher E author Coloma, Javier author Calsina, Bruna author Currás-Freixes, Maria author Letón, Rocío author Torres-Pérez, Rafael author Richter, Susan author Pita, Guillermo author Herráez, Belén author Cianchetta, Giovanni author Honrado, Emiliano author Maestre, Lorena author Urioste, Miguel author Aller, Javier author García-Uriarte, Óscar author Gálvez, María Ángeles author Luque, Raúl M author Lahera, Marcos author Moreno-Rengel, Cristina author Eisenhofer, Graeme author Montero-Conde, Cristina author Rodríguez-Antona, Cristina author Llorca Blanco, Oscar Antonio author Smolen, Gromoslaw A author Robledo Batanero, Mercedes author Cascón, Alberto author 2019-04-04 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. Am J Hum Genet . 2019 ;104(4):651-664. 10.1016/j.ajhg.2019.02.017 1537-6605 American journal of human genetics 30929736 https://hdl.handle.net/20.500.12105/23084 Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas.