First Report of Bilateral Pheochromocytoma in the Clinical Spectrum of<i>HIF2A</i>-Related Polycythemia-Paraganglioma Syndrome

Taïeb, David; Yang, Chunzhang; Delenne, B.; Zhuang, Zhengping; Barlier, Anne; Sébag, F.; Pacák, Karel

doi:10.1210/jc.2013-1217

Cited by 54 publications

(45 citation statements)

References 22 publications

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“…EPAS1 mutations have now been identified in association with a variety of phenotypes, including polycythemia without tumors (Percy et al 2008), polycythemia in combination with single or multiple pheochromocytomas/ paragangliomas, and sometimes multiple somatostatinomas (Zhuang et al 2012, Taieb et al 2013, as well as single or multiple pheochromocytomas/paragangliomas without polycythemia (Comino-Mendez et al 2013, Toledo et al 2013. Previous findings of EPAS1 mutations in different tumors from the same patient, but not in germline DNA, indicate that somatic EPAS1 mutations may occur in a cell during embryogenesis and predispose the affected tissues to tumor formation (Zhuang et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Welander¹,

Andreasson²,

Brauckhoff³

et al. 2014

Endocrine-Related Cancer

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Pheochromocytomas are neuroendocrine tumors arising from the adrenal medulla. While heritable mutations are frequently described, less is known about the genetics of sporadic pheochromocytoma. Mutations in genes involved in the cellular hypoxia response have been identified in tumors, and recently EPAS1, encoding HIF2a, has been revealed to be a new gene involved in the pathogenesis of pheochromocytoma and abdominal paraganglioma. The aim of this study was to further characterize EPAS1 alterations in non-familial pheochromocytomas. Tumor DNA from 42 adrenal pheochromocytoma cases with apparently sporadic presentation, without known hereditary mutations in predisposing genes, were analyzed for mutations in EPAS1 by sequencing of exons 9 and 12, which contain the two hydroxylation sites involved in HIF2a degradation, and also exon 2. In addition, the copy number at the EPAS1 locus as well as transcriptome-wide gene expression were studied by DNA and RNA microarray analyses, respectively. We identified six missense EPAS1 mutations, three in exon 9 and three in exon 12, in five of 42 pheochromocytomas (12%). The mutations were both somatic and constitutional, and had no overlap in 11 cases (26%) with somatic mutations in NF1 or RET. One sample had two different EPAS1 mutations, shown by cloning to occur in cis, possibly indicating a novel mechanism of HIF2a stabilization through inactivation of both hydroxylation sites. One of the tumors with an EPAS1 mutation also had a gain in DNA copy number at the EPAS1 locus. All EPAS1-mutated tumors displayed a pseudo-hypoxic gene expression pattern, indicating an oncogenic role of the identified mutations.

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Section: Discussionmentioning

confidence: 99%

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Welander¹,

Andreasson²,

Brauckhoff³

et al. 2014

Endocrine-Related Cancer

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“…WeIntroduction Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of neural crest origin. Up to an estimated 60% of PCCs/PGLs are associated with germline or somatic mutations in one many susceptibility genes (RET; VHL; NF1; SDH subunits A, B, C, D, and AF2; TMEM127; MAX; and HIF2A (EPAS1); Baysal et al 2000, Cascon et al 2009, Mannelli et al 2009, Bayley et al 2010, Burnichon et al 2010, 2012a,b, Qin et al 2010, CominoMendez et al 2011, Zhuang et al 2012, Lorenzo et al 2013, Taieb et al 2013, Toledo et al 2013. Although two decades of comprehensive study of the clinical features associated with the known PCC/PGL genes has improved patient care and genetic counseling, the highly variable behavior of these tumors continues to complicate disease management (reviewed by Raimundo et al (2011)).…”

mentioning

confidence: 99%

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Cubas¹,

Leandro‐García²,

Schiavi³

et al. 2013

Endocrine-Related Cancer

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. As microRNAs (miRNAs) are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of miRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified miRNA signatures specific to, as well as common among, the genetic groups of PCCs/PGLs. miRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD-, and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using quantitative real-time PCR. Upregulation of miR-210 in VHL-and SDHB-related PCCs/PGLs was verified, while miR-137 and miR-382 were confirmed as generally upregulated in PCCs/PGLs (except in MAX-related tumors). Also, we confirmed overexpression of miR-133b as VHL-specific miRNAs, miR-488 and miR-885-5p as RET-specific miRNAs, and miR-183 and miR-96 as SDHB-specific miRNAs. To determine the potential roles miRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment Finally, global proteomic analysis in SDHB and MAX tumors allowed us to determine that miRNA regulation occurs primarily through mRNA degradation in PCCs/PGLs, which partially confirmed our miRNA-mRNA integration results.

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“…Four patients presented with pheochromocytomas and paragangliomas associated with polycythemia. 9,10 In the present case, after surgery, the patient had a persistent although much lower elevation of plasma norepinephrine (904-1055 pg/mL). Therefore, he should be screened for the presence of somatostatinomas and pheochromocytomas, as well as residual and recurrent paragangliomas.…”

Section: Discussionmentioning

confidence: 45%

“…Several unique female-related molecular mechanisms, such as hormone and genderdependent copy number variations, may contribute to various HIF-2a signaling and tumorigenesis in the particular tumors associated with polycythemia preferentially in female patients. 10 Studying a larger number of patients with polycythemia or paraganglioma who carry HIF2A mutations could help to solve this new phenotypic puzzle.…”

Section: Discussionmentioning

confidence: 99%

Polycythemia and Paraganglioma With a Novel Somatic HIF2A Mutation in a Male

et al. 2014

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Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak-Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak-Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel-Lindau (Chuvash polycythemia), prolyl hydroxylase domain-containing protein-2, and hypoxia-inducible factor-2a (HIF2a). Somatic gain-of-function mutations in the gene encoding HIF-2a were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2a protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2a activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak-Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak-Zhuang syndrome, even in male patients. Pediatrics 2014;133:e1787-e1791

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First Report of Bilateral Pheochromocytoma in the Clinical Spectrum ofHIF2A-Related Polycythemia-Paraganglioma Syndrome

Cited by 54 publications

References 22 publications

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Polycythemia and Paraganglioma With a Novel Somatic HIF2A Mutation in a Male

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