Comino-Méndez, Iñakide Cubas, Aguirre ABernal, CarmenÁlvarez-Escolá, CristinaSánchez-Malo, CarolinaRamírez-Tortosa, César LPedrinaci, SusanaRapizzi, ElenaErcolino, ToninoBernini, GiampaoloBacca, AlessandraLetón, RocíoPita, GuillermoóAlonso, María RLeandro-García, Luis JGómez-Graña, AlvaroInglada-Pérez, LucíaMancikova, VeronikaRodríguez-Antona, CristinaMannelli, MassimoRobledo Batanero, MercedesCascon Soriano, Alberto2025-01-142025-01-142013-06-01Hum Mol Genet . 2013 Jun 1;22(11):2169-76.https://hdl.handle.net/20.500.12105/26012Pheochromocytomas (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.This work was supported in part by the Fondo de Investigaciones Sanitarias (projects PI12/00236 and PI11/01359 to A.C. and M.R., respectively), the Fundacion Mutua Madrilena (project AP2775/2008 to M. R.) and a grant from the European Community's Seventh Framework Programme (ENS@T-CANCER; HEALTH-F2-2010-259735).engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/RENAL-CELL CARCINOMASUCCINATE-DEHYDROGENASESUPPRESSOR GENEHYPOXIASDHBSUSCEPTIBILITYPATHWAYIDENTIFICATIONHIF1-ALPHAAttribution-NonCommercial-NoDerivatives 4.0 International2341831022112169-2176Human Molecular Geneticsopen access