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.

Hypoxia pathway proteins regulate the synthesis and release of epinephrine in the mouse adrenal gland

“…The latter finding is in line with results from a number of other studies that have connected HIF2α activity in the adrenal medulla or in pheochomracytomas with reduced PNMT production [9][10][11]. Tumors with pVHL mutations also overexpress HIF2 target genes such as erythropoietin (EPO), a hormone central to red blood cell (RBC) formation [12,13]. Despite these observations, studies focusing on how modulations of hypoxia pathway proteins affect adrenal function are rather sparse, and only recently has a transgenic mouse line harbouring a whole body HIF2α gain-of-function mutation been described, which showed reduced PNMT levels in the adrenal glands [14].…”

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma

“…Increased endothelial growth factor (VEGF) has been reported in malignant PHEOs and to be associated with hypoxia inducible factor (HIF) (56)(57)(58)(59). PHEOs have been well known to be associated with increased angiogenesis due to pseudohypoxic signaling pathway (60). Among the factors involved in this pathway, SDHXs were the most susceptive genes (60).…”

“…PHEOs have been well known to be associated with increased angiogenesis due to pseudohypoxic signaling pathway (60). Among the factors involved in this pathway, SDHXs were the most susceptive genes (60). Pseudohypoxic subtype has been also reported to be associated with aggressive biological behavior (60).…”

Endothelial Epas1 Deficiency Is Sufficient To Promote Parietal Epithelial Cell Activation and FSGS in Experimental Hypertension

“…Whereas gain-of-function mutations in EPAS1 are associated with paragangliomas and pheochromocytomas, 58 several genetic polymorphisms in EPAS1 and its negative regulator EGLN1, leading to downregulation of EPAS1, were described in Tibetan native highlanders, conferring adaptation to high altitude. Indeed, a gain-of-function haplotype of EGLN1, conferring lower levels of EPAS1, ten specific SNP haplotypes of EPAS1, and a 3.4-kb copy number deletion near EPAS1, were found to be significantly enriched in high-altitude Tibetans and correlated with lowered hemoglobin in this population, thus allowing adaptation to high altitude-associated hypoxia.…”