Article

From transcriptional profiling to tumor biology in pheochromocytoma and paraganglioma.

Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Endocrine Pathology (Impact Factor: 1.64). 02/2012; 23(1):15-20. DOI: 10.1007/s12022-012-9195-x
Source: PubMed

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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    • "One of them is the factor inhibiting HIF (FIH), which normally hydroxylates HIF-1α on the asparagine 803 residue. This blocks its interaction with the coactivators histone acetyltransferase p300 (p300) and cAMP-response element-binding protein (CBP) under normoxic conditions (Lando, et al. 2002; Mahon, et al. 2001) and thus inhibits the transactivation of HIF target genes (Cascon and Tennant 2012; Khan, et al. 2011). Also, SDHx mutations inhibit activity of the jumonji-domain (JmjC) histone demethylases (Cervera, et al. 2009; Xiao, et al. 2012). "
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    • "Molecular profiling studies have identified ten germline mutations that cause hereditary pheochromocytoma and paragangliomas [5], [31]. It has been suggested that these mutations can be divided into distinct molecular pathways causing errors in the HIF hypoxia-driven pathway (VHL, SDHB and SDHD) and errors in RNA synthesis and metabolism (RET, NF1, MAX, and TMEM127), while KIF1BBeta is thought to impact both pathways [32], [33]. "
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