Somatic HIF2α gain-of-function mutations in paraganglioma and somatostatinoma associated with polycythemia

Hypoxia inducible factors (HIFs) are transcription factors controlling energy, iron metabolism, erythropoiesis, and development, and, when dysregulated, contribute to tumorigenesis, cancer progression, and invasion. However, HIFα mutations have not previously been identified in any cancer. Here we report two novel somatic gain-of-function HIF2α mutations in two patients, one presenting with a paraganglioma and a second with both paraganglioma and somatostatinoma. Both mutations were shown to confer increased HIF2α activity and protein half-life. While germline mutations of regulators of HIFα, including VHL and EGLN1 , have been reported in pheochromocytomas/paragangliomas, this is the first report of a somatic gain-of-function mutation in HIF .