• Jenny Welander, Adam Andreasson, Michael Brauckhoff, Martin Bäckdahl, Catharina Larsson, Oliver Gimm, and Peter Söderkvist.
• Department of Clinical and Experimental MedicineFaculty of Health Sciences, Linköping University, Linköping SE-58185, SwedenDepartment of Oncology-PathologyKarolinska Institutet, CCK, Karolinska University Hospital, Stockholm SE-17176, SwedenDepartment of SurgeryHaukeland University Hospital, Bergen, NorwayDepartment of Clinical ScienceUniversity of Bergen, Bergen NO-5021, NorwayDepartment of Molecular Medicine and SurgeryKarolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, SwedenDepartment of SurgeryCounty Council of Östergötland, Linköping SE-58185, Sweden jenny.welander@liu.se.
• Endocr. Relat. Cancer. 2014 Jun 1; 21 (3): 495-504.

AbstractPheochromocytomas 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 HIF2α, 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 HIF2α 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 HIF2α 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. © 2014 Society for Endocrinology.

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