Germline mutations in TMEM127 confer susceptibility to pheochromocytoma

Qin, Yuejuan; Yao, Li; King, Elizabeth E.; Buddavarapu, Kalyan; Lenci, Romina; Chocrón, E. Sandra; Lechleiter, James D.; Sass, Meghan; Aronin, Neil; Schiavi, Francesca; Boaretto, Francesca; Opocher, Giuseppe; Toledo, Rodrigo A.; Toledo, S. P. A.; Stiles, Charles D.; Aguiar, Ricardo C.T.; Dahia, Patricia L.M.

doi:10.1038/ng.533

Cited by 360 publications

(394 citation statements)

References 29 publications

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“…Their diagnosis provides a correctable cause of hypertension and can prevent life-threatening complications such as heart failure and arrhythmias. Over onethird of all patients with paraganglial tumors carry germline mutations in one of the ten susceptibility genes: VHL, RET, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, MAX, and TMEM127 (Neumann et al 2002, Mannelli et al 2007, 2009, Bayley et al 2010, Burnichon et al 2010, Qin et al 2010, Comino-Mendez et al 2011. Mutations in these genes cause pheochromocytomaassociated cancer syndromes such as von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), the paraganglioma syndrome types 1-4 (PGL1-4), and the familial pheochromocytoma syndromes.…”

Section: Introductionmentioning

confidence: 99%

Long-term prognosis of patients with pediatric pheochromocytoma

Bausch¹,

Wellner²,

Bausch³

et al. 2013

Endocrine-Related Cancer

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A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-PheochromocytomaParaganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at !18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in

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Section: Introductionmentioning

confidence: 99%

Long-term prognosis of patients with pediatric pheochromocytoma

Bausch¹,

Wellner²,

Bausch³

et al. 2013

Endocrine-Related Cancer

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130

180

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“…The tumors can be a manifestation of different hereditary tumor syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1) or familial pheochromocytoma-paraganglioma syndrome, which are caused by mutations in the genes RET, VHL, NF1, and SDHx respectively (Welander et al 2011, Dahia 2014. In recent years, additional susceptibility genes for pheochromocytoma and paraganglioma have been discovered, including TMEM127 (Qin et al 2010), MAX (Comino-Mendez et al 2011), andFH (Castro-Vega et al 2014), and more rarely EGLN1 (Ladroue et al 2008) and KIF1Bb (Schlisio et al 2008). The majority of pheochromocytomas and paragangliomas are apparently sporadic, i.e.…”

Section: Introductionmentioning

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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“…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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Germline mutations in TMEM127 confer susceptibility to pheochromocytoma

Cited by 360 publications

References 29 publications

Long-term prognosis of patients with pediatric pheochromocytoma

Long-term prognosis of patients with pediatric pheochromocytoma

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

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

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