EPAS1 Mutations and Paraganglioma Insights from Recent Genetic Evidence

By Nucleati Team
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Paraganglioma, a rare neuroendocrine tumor, has long fascinated scientists and medical geneticists due to its enigmatic nature and potential genetic predisposition. Recent case reports in medical genetics have shed light on the connection between paraganglioma and mutations in the EPAS1 gene, which encodes the hypoxia-inducible factor 2-alpha (HIF-2α). By exploring these case reports and multi-patient studies, we aim to provide evidence favoring the association.

Case Reports

Patient/Family Gene/Variation Clinical Characteristics EPAS1 HGVS(es) Citation
A polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. EPAS1 (F374Y) (exon 9) mutation Polycythemia with paraganglioma. NM_001430.5(EPAS1):c.1121 T>A (p.Phe374Tyr) PubMed
Male patient with Pacak-Zhuang syndrome EPAS1, exon 12, c.1589C>A, p.Ala530Glu Congenital polycythemia, paraganglioma, somatostatinoma NM_001430.5(EPAS1):c.1589C>A (p.Ala530Glu) PubMed
Patient: age and sex not specified; daughter also studied EPAS1 germline mutations Polycythemia and cRCC. Somatic mutations in VHL, TP53 and mTOR. NM_001430.5(EPAS1):c.1609G>A (p.Gly537Arg) PubMed
Male patient with Pacak-Zhuang syndrome EPAS1 mutation in tumors Early-age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings NM_001430.5(EPAS1):c.1591C>T (p.Pro531Ser) PubMed
Two sporadic Central nervous system hemangioblastomas (CNS-HBs) HIF2A missense mutations, truncated mutations (Q557*) in HIF2A together with a VHL mutation CNS-HBs occur sporadically or as a component of von Hippel-Lindau-VHL syndrome. NM_001430.5(EPAS1):c.1121 T>A (p.Phe374Tyr) , NM_001430.5(EPAS1):c.1669 C>T (p.Gln557Ter) PubMed

Multi-Patients reports

Cohort Setup Outcome HGVS(es) Citation
Three patients with apparently sporadic PCC Whole exome sequencing using Agilent Sureselect target enrichment system and Illumina Hi seq platform 16 unique genetic variants in PCC susceptibility loci identified; NF1 Arg304Ter and RET Tyr791Phe classified as probably and possibly pathogenic, respectively - PubMed
Four unrelated patients with polycythemia, multiple PGLs, and duodenal somatostatinomas Germline and tumor tissue DNA analyzed for hypoxia-inducible factor 2 alpha (HIF2A) mutations. Prolyl hydroxylation and stability of mutant HIF2A protein, transcriptional activity of mutant HIF2A, and expression of hypoxia-related genes investigated Existence of a new syndrome with multiple PGLs and somatostatinomas associated with polycythemia resulting from somatic gain-of-function HIF2A mutations NM_001430.5(EPAS1):c.1588G>A (p.Ala530Thr), NM_001430.5(EPAS1):c.1595A>G (p.Tyr532Cys), NM_001430.5(EPAS1): c.1589C>T (p.Ala530Val), NM_001430.5(EPAS1):c.1586T>C (p.Leu529Pro) PubMed
Pheochromocytomas and paragangliomas, including germline and somatic mutations in hypoxia-related genes Exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas Somatic mutation in the HIF2A (EPAS1) gene identified in tumors, with three other HIF2A variants in sporadic cases but not in hereditary tumors or controls Somatic Mutations:
NM_001430.5(EPAS1):c.1591C>A (p.Pro531Thr), NM_001430.5(EPAS1):c.1591C>T (p.Pro531Ser) NM_001430.5(EPAS1):c.1592C>T (p.Pro531Leu) NM_001430.5(EPAS1):c.212C>A (p.Ser71Tyr)
86 unselected pheochromocytoma and paraganglioma tumor samples The study included the genes EGLN1, EPAS1, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL Germline mutations in EGLN1, KIF1Bβ, SDHA, SDHB, and TMEM127 and somatic mutations in EPAS1, KIF1Bβ, MAX, NF1, RET, and VHL Somatic Mutations:
NM_001430.5(EPAS1):c.1592C>G (p.Pro531Arg), NM_001430.5(EPAS1):c.1591C>T (p.Pro531Ser), NM_001430.5(EPAS1):c.1591C>G (p.Pro531Ala), NM_001430.5(EPAS1):c.1208T>C (p.Leu403Pro), NM_001430.5(EPAS1):c.1589C>T (p.Ala530Val), NM_001430.5(EPAS1):c.1595A>G (p.Tyr532Cys)
329 probands with single PPGL, no syndromic or family history Germline DNA tested for RET, VHL, SDH genes, TMEM127, MAX and FH. Tumors from germline-negative patients tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. Germline mutations in 14.0% of patients, more prevalent in paragangliomas than pheochromocytomas. Somatic mutations in 43% of those tested, more prevalent in pheochromocytomas than paragangliomas. Somatic mutations found in 25% of sporadic cases. HN-PGLs and T-PGLs more commonly had germline mutations. Somatic Mutations,
NM_001430.5(EPAS1):c.1592C>T (p.Pro531Leu), NM_001430.5(EPAS1):c.1606C>A (p.Asp536Tyr), NM_001430.5(EPAS1):c.1592C>T (p.Pro531Leu), NM_001430.5(EPAS1):c.1599_1604delCCCCAT (p.Ile533_Pro534del), NM_001430.5(EPAS1):c.1615G>T (p.Asp539Tyr), NM_001430.5(EPAS1):c.1592C>T (p.Pro531Leu)
719 Chinese and 919 Europeans with pathologically confirmed diagnosis of PPGL Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. - PubMed
Liver tissues from 302 HCC patients, including 104 with polycythemia HIF2A mutations were sequenced A germline HIF2A mutation was detected in one HCC patient with concurrent polycythemia. Three additional family members carried this mutation, but none exhibited polycythemia or were diagnosed with HCC. NM_001430.5(EPAS1):c.G1645A (p.Glu549Lys) PubMed
Patients with pheochromocytoma and/or paraganglioma (PPGL) and germline EPAS1 variants - Germline EPAS1 variants occurring in patients with PPGL, including the functional features in common with somatic activating mutations. NM_001430.5(EPAS1):c.739C>A (p.Arg247Ser), NM_001430.5(EPAS1):c.1121T>A (p.Phe374Tyr), NM_001430.5(EPAS1):c.581A>G (p.His194Arg), NM_001430.5(EPAS1):c.2353C>A (p.Pro785Thr), NM_001430.5(EPAS1):c.2365A>G (p.Ile789Val), NM_001430.5(EPAS1):c.2296A>C (p.Thr766Pro) PubMed
15 PPGL samples from 7 yanotic congenital heart disease (CCHD) patients. Whole-exome sequencing (WES) for somatic and germline mutations EPAS1 mutations detected in 15 out of 16 PPGL/AMH samples from 7 cases. - PubMed
42 adrenal pheochromocytoma cases with apparently sporadic presentation EPAS1/HIF2A mutations in exons 9 and 12 Pseudo-hypoxic gene expression pattern - PubMed
41 patients and 28 relatives diagnosed with an erythrocytosis associated with a germline genetic variant in EPAS1. 2 infants with severe erythrocytosis associated with a mosaic mutation present in less than 2% of the blood, one of whom later developed a paraganglioma. Gain-of-function mutations in the EPAS1/HIF2A gene Development of paraganglioma, pheochromocytoma and somatostatinoma - PubMed


The recent case reports examined in medical genetics have solidified the intriguing association between EPAS1 mutations and paraganglioma and opened doors to groundbreaking advancements. These meticulously conducted scientific studies by dedicated researchers have highlighted the crucial role of EPAS1, a key gene in the hypoxia signaling pathway, in the pathogenesis of paraganglioma. As our understanding deepens, the potential for improved diagnostics, targeted therapies, and personalized treatment approaches comes into focus. Continued scientific investigation is paramount to unraveling the precise mechanisms by which EPAS1 mutations contribute to paraganglioma development, ultimately leading to enhanced patient care and management. These insights mark significant progress and ignite enthusiasm within the scientific community, emphasizing the invaluable role of medical genetics in decoding the mysteries surrounding paraganglioma.