Predisposition to phaeochromocytoma is a feature of germline succinate dehydrogenase subunit mutations (SDHB, SDHC and SDHD), von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia (MEN) types 2A and 2B and neurofibromatosis type 1. However, although each of these disorders is associated with phaeochromocytoma they differ with respect to susceptibility to other associated tumours, However despite this clinical heterogeneity, there is evidence for shared mechanisms of tumourigenesis. Thus VHL, SDHB and SDHD inactivation have been linked to both dysregulation of the HIF-1 and HIF-2 transcription factors and a non-HIF dependent pathway involving JunB, cJun and EglN3/PHD3. The VHL tumour suppressor protein (pVHL) has multiple functions, but regulation of proteosomal degradation of HIF-1 and HIF-2 is the best studied. Most VHL mutations associated with phaeochromocytoma susceptibility result lead to loss of HIF regulation and SDH inactivation (by inhibiting the prolyl hydoxylases that modify HIF allowing pVHL to bind) also results in a pseudohypoxic gene response with overexpression of a wide range of HIF target genes including angiogenic growth factors. Although somatic VHL and SDH subunit mutations are rare in sporadic phaeochromocytoma, similar changes in gene expression to those observed in VHL-related phaeochromocytoma have also been reported in some sporadic phaeochromocytoma. However the relationship between hypoxic gene response pathways and phaeochromocytoma is complex as some germline VHL mutations associated with predisposition to phaeochromocytoma only retain the ability to regulate HIF. Thus although dysregulation of HIF pathways may not be essential for the development of phaeochromocytoma, HIF dysregulation is frequent and closely associated with phaeochromocytoma tumourigenesis.
25 - 29 Apr 2009
European Society of Endocrinology