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

Abstract

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.

• Authors: Dewi Astuti, Christopher J Ricketts, Rasheduzzaman Chowdhury, Michael A McDonough, Dean Gentle, Gail Kirby, Susanne Schlisio, Rajappa S Kenchappa, Bruce D Carter, William G Kaelin Jr, Peter J Ratcliffe, Christopher J Schofield, Farida Latif, Eamonn R Maher
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 18 Issue 1 Pg. 73-83 (Feb 2011) ISSN: 1479-6821 [Electronic] England
• PMID: 20959442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Procollagen-Proline Dioxygenase

Topics

• Adolescent
• Adrenal Gland Neoplasms (genetics, metabolism)
• Adult
• Amino Acid Sequence
• Animals
• Animals, Newborn
• Base Sequence
• Carcinoma, Renal Cell (genetics, metabolism)
• Child
• Child, Preschool
• DNA Mutational Analysis
• Female
• Genetic Predisposition to Disease
• Humans
• Kidney Neoplasms (genetics, metabolism)
• Male
• Molecular Sequence Data
• Phenotype
• Pheochromocytoma (genetics, metabolism)
• Procollagen-Proline Dioxygenase (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sequence Homology, Amino Acid
• Tumor Cells, Cultured
• Young Adult