Somatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia
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Sum m a r yHypoxia-inducible factors are transcription factors controlling energy, iron metabolism, erythropoiesis, and development.When these proteins are dysregulated, they contribute to tumorigenesis and cancer progression.However, mutations in genes encoding α subunits of hypoxia-inducible factors (HIF-α) have not previously been identified in any cancer.Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2α (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of whom had polycythemia.The two mutations were associated with increased HIF-2α activity and increased protein half-life.H ypoxia-inducible factors, originally described by Wang et al., 1 are transcription factors that respond to changes in tissue oxygen concentration.These highly conserved proteins are composed of α and β subunits.The HIF-β subunit is constitutively expressed, whereas the α subunits are inducible by hypoxia and are associated with aggressive, treatment-refractory tumors.2,3 Under normoxic conditions, HIF-1α, HIF-2α, and HIF-3α are hydroxylated on specific prolyl residues, allowing for recognition by the von Hippel-Lindau (VHL) tumorsuppressor protein, ubiquitination, and rapid degradation through the proteasome.4 Under hypoxic conditions, prolyl hydroxylation of HIF-α proteins is reduced, resulting in their stabilization and, in turn, transcription of genes involved in the hypoxia response, including angiogenesis, glycolysis, apoptosis, proliferation, and growth.5,6 Paragangliomas and pheochromocytomas are catecholamine-producing tumors derived from the chromaffin cells of extraadrenal paraganglia and the adrenal medulla.7 The pioneering work of Neumann et al. 8 showed that about one fourth of these tumors were hereditary, a fraction that was subsequently estimated to be closer to one third, on the basis of the identification of mutations in several additional genes, including SDHA, SDHAF2, TMEM127, and MAX. 9 The identification of these genetic drivers led to the demonstration of HIF-α stabilization and dysregulation in paragangliomas and pheochromocytomas harboring mutations in VHL and succinate dehydrogenase (SDH).10,11 Somatostatinomas are somatostatin-producing neuroendocrine tumors believed to originate from neural-crest cells.They are occasionally diagnosed in patients with the VHL syndrome, multiple endocrine neoplasia type 1 or 2, or neurofibromatosis type 1. 12
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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 Zhuang et al., 2012
The Results (Mutation analysis of HIF2α) identify somatic HIF2α mutations in paragangliomas from both patients, and the Discussion describes them as gain-of-function mutations. The paper does not report finding these mutations in a pheochromocytoma, so it supports only the paraganglioma portion of the attributed claim. (LLM, conf=0.88)
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- Authors
- Zhuang, Z., Yang, C., Lorenzo, F., Merino, M., Fojo, T., Kebebew, E., Popovic, V., Stratakis, C. A., Prchal, J. T., & Pacak, K.
- Affiliations
- National Institutes of Health (US)
- National Institute of Neurological Disorders and Stroke (US)
- Veterans Health Administration (US)
- National Cancer Institute (MY)
- National Cancer Institute (UA)
- University of Belgrade (RS)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- University of Utah (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-09-06
- Volume
- 367
- Issue
- 10
- Pages
- 922-930
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3432945
- OpenAlex
- W2142033642
- Cited by
- 397
- References
- 26
- Citations by year
- 2026: 22 · 2025: 12 · 2024: 22 · 2023: 18 · 2022: 20 · 2021: 29 · 2020: 24 · 2019: 24 · 2018: 32 · 2017: 43 · 2016: 27 · 2015: 31 · 2014: 47 · 2013: 42 · 2012: 2
- FWCI
- 39.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA108671)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZIAHD008735)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Keywords
- HIF-2α, paraganglioma, polycythemia, somatostatinoma, gain-of-function mutations, protein half-life, prolyl hydroxylation, VHL, succinate dehydrogenase, pheochromocytoma
- MeSH terms
- Abdominal Neoplasms, Endothelial PAS Domain-Containing Protein 1, Adolescent, Adrenal Gland Neoplasms, Adult, DNA Mutational Analysis, Female, Humans, Hydroxylation, Mutation, Pancreatic Neoplasms, Paraganglioma, Polycythemia, Somatostatinoma, Transcription, Genetic, Up-Regulation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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