Somatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia

Two patients with paraganglioma (one of whom also had somatostatinoma) were found to have mutations in HIF2A that altered HIF-2α turnover and led to excess erythropoietin production and polycythemia. Hypoxia-inducible factors, originally described by Wang et al., 1 are transcription factors that respond to changes in tissue oxygen concentration. These highly conserved proteins are composed of α and β subunits. The HIF-β subunit is constitutively expressed, whereas the α subunits are inducible by hypoxia and are associated with aggressive, treatment-refractory tumors. 2 , 3 Under normoxic conditions, HIF-1α, HIF-2α, and HIF-3α are hydroxylated on specific prolyl residues, allowing for recognition by the von Hippel–Lindau (VHL) tumor-suppressor protein, ubiquitination, and rapid degradation through the proteasome. 4 Under hypoxic conditions, prolyl hydroxylation of HIF-α proteins is reduced, resulting in their stabilization and, in turn, transcription . . .