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From Transcriptional Profiling to Tumor Biology in Pheochromocytoma and Paraganglioma

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Abstract

This review summarizes the way in which inherited mutations define global gene expression in pheochromocytoma (PCC) and paraganglioma (PGL), and how the use of gene expression analysis has advanced our understanding of these diseases. The biology of PCC and PGL tumors is diverse and it has become clear that there is no apparent single biology that defines these tumors. However, over the last 20 years, our understanding of the biology of PGL and PCC has been considerably advanced by the discovery of inherited mutations that predispose individuals to developing the disease. More recently, the use of transcriptomics to stratify tumors based on their gene expression profiles has, in particular, played a vital role in delineating novel mutations involved in the pathogenesis of these tumors. In this review, we describe our current understanding of the biology of cluster 1 (pseudohypoxic) tumors and how mutations that result in the pseudohypoxic phenotype that leads to changes in global gene expression. We also review the advances in our understanding of cluster 2 tumors, and in particular, focus on the newly described MAX tumors.

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References

  1. Eisenhofer, G., et al., Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer, 2004. 11(4): p. 897–911.

    Article  PubMed  CAS  Google Scholar 

  2. Dahia, P.L., et al., Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res, 2005. 65(21): p. 9651–8.

    Article  PubMed  CAS  Google Scholar 

  3. Huynh, T.T., et al., Transcriptional regulation of phenylethanolamine N-methyltransferase in pheochromocytomas from patients with von Hippel–Lindau syndrome and multiple endocrine neoplasia type 2. Ann N Y Acad Sci, 2006. 1073: p. 241–52.

    Article  PubMed  CAS  Google Scholar 

  4. Burnichon, N., et al., Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet, 2011. 20(20): p. 3974–85.

    Article  PubMed  CAS  Google Scholar 

  5. Lopez-Jimenez, E., et al., Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol, 2010. 24(12): p. 2382–91.

    Article  PubMed  CAS  Google Scholar 

  6. Waldmann, J., et al., Microarray analysis reveals differential expression of benign and malignant pheochromocytoma. Endocr Relat Cancer, 2010. 17(3): p. 743–56.

    Article  PubMed  CAS  Google Scholar 

  7. Brouwers, F.M., et al., Gene expression profiling of benign and malignant pheochromocytoma. Ann N Y Acad Sci, 2006. 1073: p. 541–56.

    Article  PubMed  CAS  Google Scholar 

  8. Thouennon, E., et al., Identification of potential gene markers and insights into the pathophysiology of pheochromocytoma malignancy. J Clin Endocrinol Metab, 2007. 92(12): p. 4865–72.

    Article  PubMed  CAS  Google Scholar 

  9. Dahia, P.L., et al., A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet, 2005. 1(1): p. 72–80.

    Article  PubMed  CAS  Google Scholar 

  10. Chi, J.T., et al., Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med, 2006. 3(3): p. e47.

    Article  PubMed  Google Scholar 

  11. Semenza, G.L., Targeting HIF-1 for cancer therapy. Nat Rev Cancer, 2003. 3(10): p. 721–32.

    Article  PubMed  CAS  Google Scholar 

  12. Tian, H., S.L. McKnight, and D.W. Russell, Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev, 1997. 11(1): p. 72–82.

    Article  PubMed  CAS  Google Scholar 

  13. Wang, G.L., et al., Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5510–4.

    Article  PubMed  CAS  Google Scholar 

  14. Bruick, R.K. and S.L. McKnight, A conserved family of prolyl-4-hydroxylases that modify HIF. Science, 2001. 294(5545): p. 1337–40.

    Article  PubMed  CAS  Google Scholar 

  15. Epstein, A.C., et al., C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell, 2001. 107(1): p. 43–54

    Article  PubMed  CAS  Google Scholar 

  16. Hewitson, K.S., et al., The role of iron and 2-oxoglutarate oxygenases in signalling. Biochem Soc Trans, 2003. 31(Pt 3): p. 510–5.

    PubMed  CAS  Google Scholar 

  17. Favier, J., et al., The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One, 2009. 4(9): p. e7094.

    Article  PubMed  Google Scholar 

  18. Gottlieb, E. and I.P. Tomlinson, Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer, 2005. 5(11): p. 857–66.

    Article  PubMed  CAS  Google Scholar 

  19. Astuti, D., et al., Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet, 2001. 69(1): p. 49–54.

    Article  PubMed  CAS  Google Scholar 

  20. Bayley, J.P., et al., SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol, 2010. 11(4): p. 366–72.

    Article  PubMed  CAS  Google Scholar 

  21. Baysal, B.E., et al., Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science, 2000. 287(5454): p. 848–51.

    Article  PubMed  CAS  Google Scholar 

  22. Burnichon, N., et al., SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet, 2010. 19(15): p. 3011–20.

    Article  PubMed  CAS  Google Scholar 

  23. Hao, H.X., et al., SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science, 2009. 325(5944): p. 1139–42.

    Article  PubMed  CAS  Google Scholar 

  24. Niemann, S. and U. Muller, Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet, 2000. 26(3): p. 268–70.

    Article  PubMed  CAS  Google Scholar 

  25. Selak, M.A., et al., Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 2005. 7(1): p. 77–85.

    Article  PubMed  CAS  Google Scholar 

  26. Guzy, R.D., et al., Loss of the SdhB, but Not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol, 2008. 28(2): p. 718–31.

    Article  PubMed  CAS  Google Scholar 

  27. Lando, D., et al., FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev, 2002. 16(12): p. 1466–71.

    Article  PubMed  CAS  Google Scholar 

  28. Mahon, P.C., K. Hirota, and G.L. Semenza, FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev, 2001. 15(20): p. 2675–86.

    Article  PubMed  CAS  Google Scholar 

  29. Lisy, K. and D.J. Peet, Turn me on: regulating HIF transcriptional activity. Cell Death Differ, 2008. 15(4): p. 642–9.

    Article  PubMed  CAS  Google Scholar 

  30. Cervera, A.M., et al., Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells. Mol Cancer, 2009. 8: p. 89.

    Article  PubMed  Google Scholar 

  31. Agger, K., et al., The emerging functions of histone demethylases. Curr Opin Genet Dev, 2008. 18(2): p. 159–68.

    Article  PubMed  CAS  Google Scholar 

  32. Lin, T.Y., et al., Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis. Oncogene, 2011.

  33. Sola, S., et al., p53 interaction with JMJD3 results in its nuclear distribution during mouse neural stem cell differentiation. PLoS One, 2011. 6(3): p. e18421.

    Article  PubMed  CAS  Google Scholar 

  34. Qin, Y., et al., Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet, 2010. 42(3): p. 229–33.

    Article  PubMed  CAS  Google Scholar 

  35. Segouffin-Cariou, C. and M. Billaud, Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J Biol Chem, 2000. 275(5): p. 3568–76.

    Article  PubMed  CAS  Google Scholar 

  36. Johannessen, C.M., et al., The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A, 2005. 102(24): p. 8573–8.

    Article  PubMed  CAS  Google Scholar 

  37. Yao, L., et al., Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA, 2010. 304(23): p. 2611–9.

    Article  PubMed  CAS  Google Scholar 

  38. Zhu, J., J. Blenis, and J. Yuan, Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc Natl Acad Sci U S A, 2008. 105(18): p. 6584–9.

    Article  PubMed  CAS  Google Scholar 

  39. Jimenez, R.H., et al., Regulation of gene expression in hepatic cells by the mammalian Target of Rapamycin (mTOR). PLoS One, 2010. 5(2): p. e9084.

    Article  PubMed  Google Scholar 

  40. Huang, S.C., et al., Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas. Cancer Res, 2000. 60(22): p. 6223–6.

    PubMed  CAS  Google Scholar 

  41. Huang, S.C., et al., Amplification and overexpression of mutant RET in multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma. J Clin Endocrinol Metab, 2003. 88(1): p. 459–63.

    Article  PubMed  CAS  Google Scholar 

  42. Comino-Mendez, I., et al., Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet, 2011. 43(7): p. 663–7.

    Article  PubMed  CAS  Google Scholar 

  43. Zhang, X., et al., Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res, 2010. 70(6): p. 2350–8.

    Article  PubMed  CAS  Google Scholar 

  44. Astuti, D., et al., Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour. Br J Cancer, 2005. 92(8): p. 1574–80.

    Article  PubMed  CAS  Google Scholar 

  45. Pantoja, C., et al., Inactivation of imprinted genes induced by cellular stress and tumorigenesis. Cancer Res, 2005. 65(1): p. 26–33.

    PubMed  CAS  Google Scholar 

  46. Zhang, X., et al., A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab, 2003. 88(11): p. 5119–26.

    Article  PubMed  CAS  Google Scholar 

  47. Zhao, J., et al., Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. J Clin Endocrinol Metab, 2005. 90(4): p. 2179–86.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Alberto Cascón

  2. ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain

    Alberto Cascón

  3. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK

    Daniel A Tennant

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  1. Alberto Cascón
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  2. Daniel A Tennant
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Correspondence to Daniel A Tennant.

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For submission for the Proceedings of the 3rd International Symposium on Pheochromocytoma and Paraganglioma

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Cascón, A., Tennant, D.A. From Transcriptional Profiling to Tumor Biology in Pheochromocytoma and Paraganglioma. Endocr Pathol 23, 15–20 (2012). https://doi.org/10.1007/s12022-012-9195-x

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  • DOI: https://doi.org/10.1007/s12022-012-9195-x

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