title: Hypoxia Pathway Mutations in Pheochromocytomas and Paragangliomas.
abstract: Pheochromocytomas (PCC) and sympathetic paragangliomas (PGL) are rare neuroendocrine tumors, which derive from chromaffin cells occurring in the adrenal medulla and extra-adrenal sympathetic paraganglia. PCC and PGL are often benign, catecholamine-producing tumors, responsible for a myriad of symptoms that may be potentially hazardous to the patient. In contrast, nonsecreting parasympathetic PGL, derived from chief cells, develop mainly in the head and neck region. Although PCC/PGL are more commonly sporadic tumors, germline mutations are present in up to 40% of the patients, ranking these tumors among those with the highest degree of heritability. PCC/PGL are associated with a variety of hereditary syndromes, comprising genetic alterations in RET, NF1, VHL, and SDHx genes, the last 2 being involved in regulating the hypoxia pathway. Additional hypoxia pathway-related genes have been recently associated with PCC/PGL development, namely EGLN1 and EPAS1. Thus, dysregulation of the hypoxia pathway seems to play a major role in PCC/PGL development, in particular through the stabilization of hypoxia-inducible factors and the appearance of a pseudohypoxia signature. This article is focused on reviewing the tumorigenic mechanisms resultant from VHL, SDHx, EGLN1, and EPAS1 mutations, as well as the associated tumors, namely PCC/PGL, and extra manifestations such as polycythemia. In the light of the recent discoveries, hypoxia pathway molecules appear as key players in PCC/PGL development.
authors.affiliation: Medical Faculty, University of Porto, Porto, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Amorim-Pires
authors.forename: Joana
authors.initials: J
authors.lastname: Peixoto
authors.forename: Jorge
authors.initials: J
authors.lastname: Lima
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009389:Neovascularization, Pathologic; D010235:Paraganglioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D010673:Pheochromocytoma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology