title: Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.
abstract: 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.
authors: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre CNIO, Madrid 28029, Spain.
authors: Iñaki
authors: I
authors: Comino-Méndez
authors: Aguirre A
authors: AA
authors: de Cubas
authors: Carmen
authors: C
authors: Bernal
authors: Cristina
authors: C
authors: Álvarez-Escolá
authors: Carolina
authors: C
authors: Sánchez-Malo
authors: César L
authors: CL
authors: Ramírez-Tortosa
authors: Susana
authors: S
authors: Pedrinaci
authors: Elena
authors: E
authors: Rapizzi
authors: Tonino
authors: T
authors: Ercolino
authors: Giampaolo
authors: G
authors: Bernini
authors: Alessandra
authors: A
authors: Bacca
authors: Rocío
authors: R
authors: Letón
authors: Guillermoó
authors: G
authors: Pita
authors: María R
authors: MR
authors: Alonso
authors: Luis J
authors: LJ
authors: Leandro-García
authors: Alvaro
authors: A
authors: Gómez-Graña
authors: Lucía
authors: L
authors: Inglada-Pérez
authors: Veronika
authors: V
authors: Mancikova
authors: Cristina
authors: C
authors: Rodríguez-Antona
authors: Massimo
authors: M
authors: Mannelli
authors: Mercedes
authors: M
authors: Robledo
authors: Alberto
authors: A
authors: Cascón
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics*; D002869:Chromosome Aberrations; D002889:Chromosomes, Human, Pair 2; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010236:Paraganglioma, Extra-Adrenal / Q000150:complications* / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D011086:Polycythemia / Q000150:complications* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1