OR29-6 A new syndrome of paraganglioma and somatostatinoma associated with polycythemia

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR29-Adrenal Tumors & Pheochromocytoma
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:30 PM
Room 134 (Moscone Center)
Karel Pacak*1, Ivana Jochmanova2, Tamara Prodanov2, Chunzhang Yang3, Maria Merino4, Tito Fojo4, Josef T Prchal5, Arthur S Tischler6, Ronald M Lechan6 and Zhengping Zhuang3
1National Institutes of Health (NIH), Bethesda, MD, 2Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 3National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 4National Cancer Institute, National Institutes of Health, Bethesda, MD, 5University of Utah School of Medicine and VAH, Salt Lake City, UT, 6Tufts Medical Center, Boston, MA
Four unrelated patients with a similar cluster of disease phenotypes were investigated with thorough clinical and molecular evaluation. Using unique imaging and biochemistry, they were found to have multiple paragangliomas and multiple duodenal somatostatinomas associated with polycythemia due to novel somatic gain-of-function hypoxia-inducible factor 2a (HIF2A) mutations. Each patient carried an identical unique mutation in both types of tumors, but not in germline DNA. The HIF2A mutations of these patients were clustered adjacent to an oxygen-sensing proline residue, affecting HIF-2α interaction with the prolyl hydroxylase domain-2 containing protein, decreasing the hydroxylation of HIF-2α and reducing its affinity for von Hippel-Lindau protein and its degradation. An increase in the half-life of HIF-2α was associated with an up-regulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1 in tumors.

Conclusion The present findings indicate the existence of a new neuroendocrine tumor syndrome presenting with multiple paragangliomas and somatostatinomas associated with polycythemia. Furthermore, they share a common genetic denominator, HIF2A mutations, that contribute to the pathogenesis of the tumors and polycythemia. The study suggests that patients with polycythemia should be screened for the presence of NETs or conversely, patients with multiple apparently sporadic paragangliomas with or without polycythemia should be screened for the presence of somatostatinomas and HIF2A mutations. Finally, these findings open a new avenue for paraganglioma research that the pathogenesis of other sporadic and hereditary tumors are indeed interconnected via HIF signaling and support the use of new therapeutic options targeting this specific pathway.

Nothing to Disclose: KP, IJ, TP, CY, MM, TF, JTP, AST, RML, ZZ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Instititue of Neurological Disorders and Stroke at the National Institutes of Health.
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