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Expression of HIF-1, HIF-2 (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations

Molecular and Population Genetics Laboratory (P.J.P., I.P.M.T.), Histopathology Service (G.E.), In Situ Hybridisation Service (R.P., T.H., R.J., P.S.), and Bioinformatics & Biostatistics Service (G.K.), London Research Institute, Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX, United Kingdom; Imperial College Department of Histopathology (M.E.-B., G.W.S.), Division of Investigative Science, Hammersmith Hospital, DuCane Road, London W12 0NN, United Kingdom; Department of Otolaryngology (M.J.G.), Guy’s Hospital, London SE1 9RT, United Kingdom; Department of Clinical Genetics (J.B., S.V.H.), St. George’s Hospital, London SW17 0RE, United Kingdom; and Cancer Research UK Renal Molecular Oncology Group (P.K., F.L., E.R.M.), Section of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham B15 2TT, United Kingdom

Address all correspondence and requests for reprints to: Professor Eamonn R. Maher, Cancer Research UK Renal Molecular Oncology Group, Section of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham B15 2TT, UK. E-mail: e.r.maher{at}bham.ac.uk.

Context: Activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and a HIF-independent defect in developmental apoptosis have been implicated in the pathogenesis of pheochromocytoma (PCC) associated with VHL, SDHB, and SDHD mutations.

Objective: Our objective was to compare protein (HIF-1, EPAS1, SDHB, JunB, CCND1, CD34, CLU) and gene (VEGF, BNIP3) expression patterns in VHL and SDHB/D associated tumors.

Results: Overexpression of HIF-2 was relatively more common in VHL than SDHB/D PCC (12 of 13 vs. 14 of 20, P = 0.02), whereas nuclear HIF-1 staining was relatively more frequent in SDHB/D PCC (19 of 20 vs. 13 of 16, P = 0.04). In addition, CCND1 and VEGF expression (HIF-2 target genes) was significantly higher in VHL than in SDHB/D PCC. These findings suggest that VHL inactivation leads to preferential HIF-2 activation and CCND1 expression as described previously in VHL-defective renal cell carcinoma cell lines but not in other cell types. These similarities between the downstream consequences of VHL inactivation and HIF dysregulation in renal cell carcinoma and PCC may explain how inactivation of the ubiquitously expressed VHL protein results in susceptibility to specific tumor types. Both VHL and SDHB/D PCC demonstrated reduced CLU and SDHB expression. SDHB PCC are associated with a high risk of malignancy, and expression of (proapototic) BNIP3 was significantly lower in SDHB than VHL PCC.

Conclusion: Although inactivation of VHL and SDHB/D may disrupt similar HIF-dependent and HIF-independent signaling pathways, their effects on target gene expression are not identical, and this may explain the observed clinical differences in PCC and associated tumors seen with germline VHL and SDHB/D mutations.

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