Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility

• Published in: Endocrine-related cancer Vol. 18; no. 1; pp. 73 - 83
• Main Authors: Astuti, Dewi, Ricketts, Christopher J, Chowdhury, Rasheduzzaman, McDonough, Michael A, Gentle, Dean, Kirby, Gail, Schlisio, Susanne, Kenchappa, Rajappa S, Carter, Bruce D, Kaelin, William G, Ratcliffe, Peter J, Schofield, Christopher J, Latif, Farida, Maher, Eamonn R
• Format: Journal Article
• Language: English
• Published: England Society for Endocrinology 01-02-2011; BioScientifica
• Subjects: Adolescent; Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - metabolism; Adult; Amino Acid Sequence; Animals; Animals, Newborn; Base Sequence; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Male; Medicin och hälsovetenskap; Molecular Sequence Data; Phenotype; Pheochromocytoma - genetics; Pheochromocytoma - metabolism; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; Rats; Rats, Sprague-Dawley; Regular Papers; Sequence Homology, Amino Acid; Tumor Cells, Cultured; Young Adult
• ISSN: 1351-0088; 1479-6821; 1479-6821
• DOI: 10.1677/ERC-10-0113

Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-α transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC.