Abstract
Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A F374Y (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A F374Y may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development.
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Acknowledgments
JTP is supported by NIH-P01CA108671, VA Merit Review Award and University of Utah Seed Grant Program for studies of hypoxic adaptation. MG is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia (#1006407). KP, ZZ, CY, and TH are supported, in part, by the Intramural Research Program of the NIH, NICHD, and NINDS.
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Authors declare no competing financial interests.
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Karel Pacak and Josef T. Prchal are senior authors.
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Lorenzo, F.R., Yang, C., Ng Tang Fui, M. et al. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med 91, 507–512 (2013). https://doi.org/10.1007/s00109-012-0967-z
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DOI: https://doi.org/10.1007/s00109-012-0967-z