<i>PHD2</i>Mutation and Congenital Erythrocytosis with Paraganglioma

Ladroue, Charline; Carcenac, Romain; Leporrier, M; Gad, Sophie; Hello, C. Le; Galateau-Salle, Françoise; Feunteun, Jean; Pouysségur, Jacques; Richard, Stéphane; Gardie, Betty

doi:10.1056/nejmoa0806277

Cited by 289 publications

(243 citation statements)

References 21 publications

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“…For PREF1 and THY1, the counterstaining was performed by incubating the slides for 4 For PREF1 and THY1, 1C represents a weak resultant score (staining intensity multiplied by the quantity score), 2C represents a moderate resultant score, and 3C represents a strong resultant score. 5 Hematopoietic stem cell.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations

Oudijk

Neuhofer

Lichtenauer

et al. 2015

European Journal of Endocrinology

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Objective: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs. Design: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers. Results: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in !10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease. Conclusion: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.

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Section: Immunohistochemistrymentioning

confidence: 99%

Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations

Oudijk

Neuhofer

Lichtenauer

et al. 2015

European Journal of Endocrinology

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“…In addition, germline mutations in KIF1Bβ have been found in patients with PCCs, neuroblastomas and other neural and non-neural tumors [12,13]. More recently, EPAS1/HIF2A germline mutations were found in patients with PCCs/PGLs and polycythemia (polycythemia-paraganglioma syndrome) [14] Susceptibility genes for which no syndromic form has been described yet include EGLN1 [15], TMEM127 [16] and MAX [17].…”

Section: Introductionmentioning

confidence: 99%

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

et al. 2013

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Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel Lindau (VHL) syndrome. In VHL, only about 30% of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation as well as mRNA expression of SDHAF2 and SDHD was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to a significant decrease (p<0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression.In addition, the lack of mutations and promoter methylation in the investigated samples indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

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“…EGLN1 (egl-nine-homolog-1) gene, also termed PHD2, is located on chromosome 1q42.1, encodes a prolyl hydroxylase, which has a crucial function in the oxygendependent proline hydroxylation of the HIF-α pathway. Therefore, through similar pseudohypoxic mechanisms as in SDH, EGLN1 mutations can give rise to familial paraganglioma (47).…”

Section: Other Genesmentioning

confidence: 97%

“…Most of the extra-adrenal tumours are due to mutations in SDH genes (4,7,36,37,40,53). Apart from which, extra-adrenal tumours were also found in rare EGLN1 mutation (47). Although, rare extra adrenal tumours can also be found in VHL, TMEM 127, NF1, and RET mutations as well (11,12,14,21,26,42,53).…”

Section: Location Of the Tumourmentioning

confidence: 99%

The clinical genetics of phaeochromocytoma and paraganglioma

Gunawardane

Grossman

2017

Arch. Endocrinol. Metab.

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Phaeochromocytoma and paraganglioma are rare catecholamine-producing tumours, recognised to have one of the richest hereditary backgrounds of all neoplasms, with germline mutations seen in approximately 30% of patients. They can be a part of genetic syndromes such as MEN 2 or Neurofibromatosis type 1, or can be found as apparently sporadic tumours. Germline mutations are almost always found in syndromic patients. Nonetheless, apparently sporadic phaeochromocytoma too show high germline mutation rates. Early detection of a genetic mutation can lead to early diagnosis of further tumours via surveillance, early treatment and better prognosis. Apart from this, the genetic profile has important relevance for tumour location and biochemical profile, and can be a useful predictor of future tumour behaviour. It also enables family screening and surveillance. Moreover, recent studies have demonstrated significant driver somatic mutations in up to 75% of all tumours. Arch Endocrinol Metab. 2017;61(5):490-500

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PHD2Mutation and Congenital Erythrocytosis with Paraganglioma

Cited by 289 publications

References 21 publications

Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations

Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

The clinical genetics of phaeochromocytoma and paraganglioma

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