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Frequent EPAS1/HIF2 alpha exons 9 and 12 mutations in non-familial pheochromocytoma
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Karolinska University Hospital, Sweden.
Haukeland Hospital, Norway; University of Bergen, Norway.
Karolinska University Hospital, Sweden.
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2014 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 3, 495-504 p.Article in journal (Refereed) Published
Abstract [en]

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 HIF2 alpha, 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.

Place, publisher, year, edition, pages
BioScientifica , 2014. Vol. 21, no 3, 495-504 p.
Keyword [en]
EPAS1; HIF2A; pheochromocytoma; mutation; copy number; gene expression
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-112842DOI: 10.1530/ERC-13-0384ISI: 000344787700030PubMedID: 24741025OAI: diva2:776757

Funding Agencies|University of Linkoping; Swedish Cancer Foundation; Swedish Research Council; Cancer Society in Stockholm; StratCan at Karolinska Institutet

Available from: 2015-01-08 Created: 2014-12-17 Last updated: 2015-03-04
In thesis
1. Genetic Alterations in Pheochromocytoma and Paraganglioma
Open this publication in new window or tab >>Genetic Alterations in Pheochromocytoma and Paraganglioma
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pheochromocytomas and paragangliomas are neuroendocrine tumors that arise from neural crest-derived cells of the adrenal medulla and the extra-adrenal paraganglia. They cause hypertension due to an abnormally high production of catecholamines (mainly adrenaline and noradrenaline), with symptoms including recurrent episodes of headache, palpitations and sweating, and an increased risk of cardiovascular disease. Malignancy in the form of distant metastases occurs in 10-15% of the patients. The malignant cases are difficult to predict and cure, and have a poor prognosis. About a third of pheochromocytomas and paragangliomas are caused by hereditary mutations in a growing list of known susceptibility genes. However, the cause of the remaining, sporadic, tumors is still largely unknown. The aim of this thesis project has been to further characterize the genetic background of pheochromocytomas and paragangliomas, with a focus on the sporadic tumors.

First, we investigated the role of the genes known from the familial tumors in the sporadic form of the disease. By studying mutations, copy number variations, DNA methylation and gene expression, we found that many of the known susceptibility genes harbor somatic alterations in sporadic pheochromocytomas. Particularly, we found that the NF1 gene, which plays an important role in suppressing cell growth and proliferation by regulating the RASMAPK pathway, was inactivated by mutations in more than 20% of the cases. The mutations occurred together with deletions of the normal allele and were associated with a reduced NF1 gene expression and a specific hormone profile. We also detected activating mutations in the gene EPAS1, which encodes HIF-2α, in a subset of sporadic cases. Microarray analysis of gene expression showed that several genes involved in angiogenesis and cell metabolism were upregulated in EPAS1-mutated tumors, which is in agreement with the role of HIF-2α in the cellular response to hypoxia. In order to comprehensively investigate all the known susceptibility genes in a larger patient cohort, we designed a targeted next-generation sequencing approach and could conclude that it was fast and cost-efficient for genetic testing of pheochromocytomas and paragangliomas. The results showed that about 40% of the sporadic cases had mutations in the tested genes. The majority of the mutations were somatic, but some apparently sporadic cases in fact carried germline mutations. Such knowledge of the genetic background can be of importance to facilitate early detection and correct treatment of pheochromocytomas, paragangliomas and potential co-occurring cancers, and also to identify relatives that might be at risk. By sequencing all the coding regions of the genome, the exome, we then identified recurrent activating mutations in a novel gene, in which mutations have previously only been reported in subgroups of brain tumors. The identified mutations are proposed to cause constitutive activation of the encoded receptor tyrosine kinase, resulting in the activation of downstream kinase signaling pathways that promote cell growth and proliferation.

In summary, the studies increase our biological understanding of pheochromocytoma and paraganglioma, and possibly also co-occurring cancers in which the same genes and pathways are involved. Together with the findings of other scientific studies, our results may contribute to the development of future treatment options.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 64 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1439
Pheochromocytoma; paraganglioma; genetics; sequencing; cancer; mutation
National Category
Clinical Medicine
urn:nbn:se:liu:diva-114806 (URN)10.3384/diss.diva-114806 (DOI)978-91-7519-145-4 (print) (ISBN)
Public defence
2015-04-09, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2016-04-07Bibliographically approved

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Welander, JennyGimm, OliverSöderkvist, Peter
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Division of Cell BiologyFaculty of Health SciencesDivision of Clinical SciencesDepartment of Surgery in LinköpingDepartment of Clinical Pathology and Clinical Genetics
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Endocrine-Related Cancer
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