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 increa…
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Somatic gain-of-function mutations in HIF2A have been discovered in pheochromocytomas and paragangliomas.
“Somatic gain-of-function mutations in HIF2A have been discovered in pheochromocytomas and paragangliomas (Zhuang et al., 2012;Comino-Mendez et al., 2013;Lorenzo et al., 2013;Taieb et al., 2013;Toledo et al., 2013;Yang et al., 2013), while high HIF-2α expression is associated with poor survival in patients with neuroblastoma (Holmquist-Mengelbier et al., 2006).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Comino-Mendez et al., 2013
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References 42 · Cited by 169
- Authors
- Comino-Méndez, I., de Cubas, A. A., Bernal, C., Álvarez-Escolá, C., Sánchez-Malo, C., Ramírez-Tortosa, C. L., Pedrinaci, S., Rapizzi, E., Ercolino, T., Bernini, G., Bacca, A., Letón, R., Pita, G., Alonso, M. R., Leandro-García, L. J., Gómez-Graña, Á., Inglada-Pérez, L., Mancikova, V., Rodríguez-Antona, C., Mannelli, M., Robledo, M., & Cascón, A.
- Affiliations
- Hospital Universitario 12 De Octubre (ES)
- Complejo Hospitalario de Jaén (ES)
- Universidad de Granada (ES)
- University of Florence (IT)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- University of Pisa (IT)
- Spanish National Cancer Research Centre (ES)
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-14
- Volume
- 22
- Issue
- 11
- Pages
- 2169-2176
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2098785387
- Cited by
- 169
- References
- 42
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 8 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 13 · 2017: 22 · 2016: 16 · 2015: 19 · 2014: 17 · 2013: 11
- FWCI
- 20.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- pheochromocytoma, paraganglioma, EPAS1, HIF-2α, somatic mutations, hypoxia, congenital erythrocytosis, copy number alterations, PCSK6, genetic diagnosis, chromaffin cell tumors
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adolescent, Adult, Aged, Amino Acid Sequence, Hypoxia, Chromosome Aberrations, Chromosomes, Human, Pair 2, Female, Humans, Male, Middle Aged, Mutation, Paraganglioma, Extra-Adrenal, Pheochromocytoma, Polycythemia, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Basic Helix-Loop-Helix Proteins, Protein Interaction Domains and Motifs, Young Adult
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