The occurrence of more than two distinct types of tumors is unusual in an individual patient, except in hereditary cancer syndromes.
Four unrelated patients were initially referred to our institute and found to have similar disease clusters with multiple paragangliomas and somatostatinomas associated with polycythemia.
Through further investigation, we discovered that all of the tumors in these patients carried hypoxia-inducible factor 2 alpha (HIF2A) mutations.
The HIF2A mutations were clustered adjacent to an oxygen-sensing proline residue, affecting HIF2α interaction with the prolyl hydroxylase domain 2–containing protein, decreasing the hydroxylation of HIF2α, and reducing HIF2α affinity for the von Hippel–Lindau protein and its degradation.
This leads to an increase in the half-life of HIF2α in the tumors resulting in upregulation of the hypoxia-related genes EPO, VEGFA, GLUT1, and END1, a state termed “pseudo-hypoxia”.
Hypoxia inducible factors (HIFs) including HIF2α are known to control the cellular response to hypoxia, and when dysregulated, can contribute to tumorigenesis.
Our findings indicate the existence of a new syndrome with multiple paragangliomas and somatostatinomas associated with polycythemia.
The underlying pathogenesis shares the same mechanism as somatic gain-of-function HIF2A mutations, in which pseudo-hypoxia signaling is triggered, resulting in up-regulation of hypoxia-related genes, including EPO and genes important in tumor formation. |
