Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

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)...

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Detalles Bibliográficos
Autores: Comino-Méndez, Iñaki, de Cubas, Aguirre A, Bernal, Carmen, Álvarez-Escolá, Cristina, Sánchez-Malo, Carolina, Ramírez-Tortosa, César L, Pedrinaci, Susana, Rapizzi, Elena, Ercolino, Tonino, Bernini, Giampaolo, Bacca, Alessandra, Letón, Rocío, Pita, Guillermoó, Alonso, María R, Leandro-García, Luis J, Gómez-Graña, Alvaro, Inglada-Pérez, Lucía, Mancikova, Veronika, Rodríguez-Antona, Cristina, Mannelli, Massimo, Robledo Batanero, Mercedes, Cascon Soriano, Alberto
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26012
Acceso en línea:https://hdl.handle.net/20.500.12105/26012
Access Level:acceso abierto
Palabra clave:RENAL-CELL CARCINOMA
SUCCINATE-DEHYDROGENASE
SUPPRESSOR GENE
HYPOXIA
SDHB
SUSCEPTIBILITY
PATHWAY
IDENTIFICATION
HIF1-ALPHA
Descripción
Sumario: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.

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