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

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.

[1]  P. Camacho.  Clinical Endocrinology and Metabolism , 2011 .

[2]  Haiguo Wu,et al.  Targeted high throughput sequencing of a cancer-related exome subset by specific sequence capture with a fully automated microarray platform. , 2010, Genomics.

[3]  Fiona Douglas,et al.  Tumor risks and genotype–phenotype–proteotype analysis in 358 patients with germline mutations in SDHB and SDHD , 2010, Human mutation.

[4]  C. Ricketts,et al.  Identification of Candidate Tumour Suppressor Genes Frequently Methylated in Renal Cell Carcinoma , 2009, Oncogene.

[5]  Gurpreet W. Tang,et al.  Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes , 2009, Nature.

[6]  C. Domene,et al.  Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. , 2009, Structure.

[7]  J. Stamatoyannopoulos,et al.  Power of deep, all-exon resequencing for discovery of human trait genes , 2009, Proceedings of the National Academy of Sciences.

[8]  F. Galateau-Sallé,et al.  PHD2 mutation and congenital erythrocytosis with paraganglioma. , 2008, The New England journal of medicine.

[9]  S. Richard,et al.  Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN , 2008, Clinical Cancer Research.

[10]  C. Ricketts,et al.  Germline SDHB mutations and familial renal cell carcinoma. , 2008, Journal of the National Cancer Institute.

[11]  M. Meyerson,et al.  The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. , 2008, Genes & development.

[12]  P. Carmeliet,et al.  Abnormal Sympathoadrenal Development and Systemic Hypotension in PHD3−/− Mice , 2008, Molecular and Cellular Biology.

[13]  H. Wajcman,et al.  Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. , 2008, Blood cells, molecules & diseases.

[14]  Eleanor A. L. Bagg,et al.  Kinetic Rationale for Selectivity toward N- and C-terminal Oxygen-dependent Degradation Domain Substrates Mediated by a Loop Region of Hypoxia-Inducible Factor Prolyl Hydroxylases* , 2008, Journal of Biological Chemistry.

[15]  W. Krek,et al.  Multitasking by pVHL in tumour suppression. , 2007, Current opinion in cell biology.

[16]  L. del Peso,et al.  Identification of a region on hypoxia-inducible-factor prolyl 4-hydroxylases that determines their specificity for the oxygen degradation domains. , 2007, The Biochemical journal.

[17]  Min Gyu Lee,et al.  Drosophila UTX Is a Histone H3 Lys27 Demethylase That Colocalizes with the Elongating Form of RNA Polymerase II , 2007, Molecular and Cellular Biology.

[18]  M. McMullin,et al.  A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. , 2007, Blood.

[19]  M. Mannelli,et al.  Genetic screening for pheochromocytoma: should SDHC gene analysis be included? , 2007, Journal of Medical Genetics.

[20]  E. Maher,et al.  Genotype–phenotype correlations in von Hippel‐Lindau disease , 2004, Human mutation.

[21]  G. Stamp,et al.  Expression of HIF-1α, HIF-2α (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations , 2006 .

[22]  J. Zondlo,et al.  Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  P. Barker,et al.  Ligand-Dependent Cleavage of the P75 Neurotrophin Receptor Is Necessary for NRIF Nuclear Translocation and Apoptosis in Sympathetic Neurons , 2006, Neuron.

[24]  C. Taylor,et al.  Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. , 2006, Cancer research.

[25]  M. McMullin,et al.  A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Stamp,et al.  Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. , 2006, The Journal of clinical endocrinology and metabolism.

[27]  C. Eng,et al.  Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. , 2005, JAMA.

[28]  W. Kaelin,et al.  Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. , 2005, Cancer cell.

[29]  Patrick H. Maxwell,et al.  Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma , 2005, Molecular and Cellular Biology.

[30]  K. Schlingensiepen,et al.  The role of Jun transcription factor expression and phosphorylation in neuronal differentiation, neuronal cell death, and plastic adaptationsin vivo , 1994, Cellular and molecular neurobiology.

[31]  Eyal Gottlieb,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[32]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[33]  J. Schipper,et al.  Germline Mutations in Non-syndromic Pheochromocytoma , 2004 .

[34]  A. Harris,et al.  Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor* , 2004, Journal of Biological Chemistry.

[35]  H. Moch,et al.  Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma , 2004, Journal of Clinical Pathology.

[36]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.

[37]  W. Kaelin,et al.  Inhibition of HIF2α Is Sufficient to Suppress pVHL-Defective Tumor Growth , 2003, PLoS biology.

[38]  J. Prchal,et al.  Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. , 2003, American journal of human genetics.

[39]  P. Sutphin,et al.  Role of Prolyl Hydroxylation in Oncogenically Stabilized Hypoxia-inducible Factor-1α* , 2002, The Journal of Biological Chemistry.

[40]  R. Wisdom,et al.  c-jun is essential for sympathetic neuronal death induced by NGF withdrawal but not by p75 activation , 2002, The Journal of cell biology.

[41]  J. Schipper,et al.  Germ-line mutations in nonsyndromic pheochromocytoma. , 2002, The New England journal of medicine.

[42]  S. McKnight,et al.  A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF , 2001, Science.

[43]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[44]  P. Ratcliffe,et al.  Independent function of two destruction domains in hypoxia‐inducible factor‐α chains activated by prolyl hydroxylation , 2001, The EMBO journal.

[45]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[46]  S. White,et al.  Dynamic, site-specific interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor protein. , 2001, Cancer research.

[47]  P. Ratcliffe,et al.  Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. , 2001, Human molecular genetics.

[48]  M. Ivan,et al.  von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. , 2001, Human molecular genetics.

[49]  D. Evans,et al.  Germline SDHD mutation in familial phaeochromocytoma , 2001, The Lancet.

[50]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[51]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[52]  C. Eng,et al.  Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. , 2000, Cancer research.

[53]  B. Devlin,et al.  Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. , 2000, Science.

[54]  C. Wykoff,et al.  The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis , 1999, Nature.

[55]  B. Ponder,et al.  Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. , 1997, Human molecular genetics.

[56]  S. Chew,et al.  Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. , 1995, Journal of medical genetics.

[57]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[58]  B. Ponder,et al.  Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma. , 1995, Journal of medical genetics.

[59]  L. Rubin,et al.  A c-jun dominant negative mutant protects sympathetic neurons against programmed cell death , 1995, Neuron.

[60]  S. Estus,et al.  Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis , 1994, The Journal of cell biology.

[61]  M. Ferguson-Smith,et al.  Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. , 1994, Human molecular genetics.

[62]  J. Brooks,et al.  Mutations of the VHL tumour suppressor gene in renal carcinoma , 1994, Nature Genetics.

[63]  J. Gnarra,et al.  Identification of the von Hippel-Lindau disease tumor suppressor gene. , 1993, Science.

[64]  M. Ferguson-Smith,et al.  Clinical features and natural history of von Hippel-Lindau disease. , 1990, The Quarterly journal of medicine.

[65]  B. Cowan,et al.  A Family Is , 1981 .

[66]  C. Perry.  Clinical Features , 2004, Bristol medico-chirurgical journal.