Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia

Yang, Chunzhang; Zhuang, Zhengping; Fliedner, Stephanie; Shankavaram, Uma; Sun, Michael; Bullova, Petra; Zhu, Roland; Elkahloun, Abdel G.; Kourlas, Peter J.; Merino, María J.; Kebebew, Electron; Pacák, Karel

doi:10.1007/s00109-014-1205-7

Cited by 120 publications

(114 citation statements)

References 33 publications

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“…So far, 16 genes are known to be associated with PCCs/PGLs: SDHA, SDHB, SDHC, SDHD and SDHAF2 (together SDHx), VHL, RET, NF1, TMEM127, MAX, KIF1B, and PHD2, as well as the recently identified HIF2A (2, 4, 5, 6), HRAS (7), FH (8), and PHD1 (9). The identification of distant metastases is still the only proof of malignancy in PCCs/PGLs, and because treatment options are limited, finding an appropriate strategy poses a clinical challenge (10).…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…'Initial diagnosis' was revised after some weeks to 12 years (last column), but always before entry into the registry. (Toledo et al 2013, Castro-Vega et al 2014, Yang et al 2015, because such patients seem to have only extremely rare head and neck paragangliomas: in addition, EPAS1 mutations are typically associated with polycythemia, which was not seen in any of our registrants. Genomic DNA was obtained from EDTA-anticoagulated whole blood.…”

Section: Genetic Mutation Analysesmentioning

confidence: 83%

“…PGL 1 to PGL 5 are associated with germline mutations of the genes encoding succinate dehydrogenase subunit D, SDHD (PGL 1), succinate dehydrogenase complex assembly factor 2, SDHAF2 (PGL 2), succinate dehydrogenase subunit C, SDHC (PGL 3), succinate dehydrogenase subunit B, SDHB (PGL 4), and succinate dehydrogenase subunit A, SDHA (PGL 5), the SDHx genes (Zantour et al 2004). Heritable non-SDHx paraganglioma can also occur in tumor syndromes mainly associated with pheochromocytomas such as von Hippel-Lindau disease (associated with mutations of the VHL gene), multiple endocrine neoplasia type 2 (RET gene), and neurofibromatosis type 1 (NF1 gene) , Neumann et al 2009, Burnichon et al 2010, Castro-Vega et al 2014, Yang et al 2015. In patients carrying germline mutations of the new susceptibility genes FH, PHD1 (EGLN2), and PHD2 (EGLN1), head and neck paragangliomas have not been reported (Castro-Vega et al 2014, Yang et al 2015.…”

Section: Introductionmentioning

confidence: 99%

“…Heritable non-SDHx paraganglioma can also occur in tumor syndromes mainly associated with pheochromocytomas such as von Hippel-Lindau disease (associated with mutations of the VHL gene), multiple endocrine neoplasia type 2 (RET gene), and neurofibromatosis type 1 (NF1 gene) , Neumann et al 2009, Burnichon et al 2010, Castro-Vega et al 2014, Yang et al 2015. In patients carrying germline mutations of the new susceptibility genes FH, PHD1 (EGLN2), and PHD2 (EGLN1), head and neck paragangliomas have not been reported (Castro-Vega et al 2014, Yang et al 2015. Somatic mutations of the HIF2A (EPAS1) gene have been reported in abdominal paraganglial tumors but not in head and neck paragangliomas (Toledo et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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A registry-based study of thyroid paraganglioma: histological and genetic characteristics

Dobschuetz

Leijon

Schalin‐Jäntti

et al. 2015

Endocrine-Related Cancer

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“…Under hypoxic conditions, hydroxylation of the HIF-1a subunit is suppressed, leading to increased levels of HIF that regulate the expression of many target genes. (Jochmanová et al 2013, Yang et al 2015.…”

Section: :6mentioning

confidence: 99%

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Angelousi¹,

Dimitriadis²,

Zografos³

et al. 2017

Endocrine-Related Cancer

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Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

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Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia

Abstract: • A novel germ-l i n e PHD1 mutation causing heochromocytoma/paraganglioma and polycythemia. • Increased EPOR activity and inappropriate hypersensitivity of erythroid progenitors to EPO.

Cited by 120 publications

References 33 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

A registry-based study of thyroid paraganglioma: histological and genetic characteristics

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

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