2026-04-26T23:12:00Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260122025-12-18T12:54:32Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Comino-Méndez, Iñaki author de Cubas, Aguirre A author Bernal, Carmen author Álvarez-Escolá, Cristina author Sánchez-Malo, Carolina author Ramírez-Tortosa, César L author Pedrinaci, Susana author Rapizzi, Elena author Ercolino, Tonino author Bernini, Giampaolo author Bacca, Alessandra author Letón, Rocío author Pita, Guillermoó author Alonso, María R author Leandro-García, Luis J author Gómez-Graña, Alvaro author Inglada-Pérez, Lucía author Mancikova, Veronika author Rodríguez-Antona, Cristina author Mannelli, Massimo author Robledo Batanero, Mercedes author Cascon Soriano, Alberto author 2013-06-01 Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease. Hum Mol Genet . 2013 Jun 1;22(11):2169-76. https://hdl.handle.net/20.500.12105/26012 23418310 Human Molecular Genetics RENAL-CELL CARCINOMA SUCCINATE-DEHYDROGENASE SUPPRESSOR GENE HYPOXIA SDHB SUSCEPTIBILITY PATHWAY IDENTIFICATION HIF1-ALPHA Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.