An Update on the Genetics of Paraganglioma, Pheochromocytoma, and Associated Hereditary Syndromes
- 10 February 2012
- journal article
- review article
- Published by Georg Thieme Verlag KG in Hormone and Metabolic Research
- Vol. 44 (05), 328-333
- https://doi.org/10.1055/s-0031-1301302
Abstract
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are catecholamine-secreting tumors of neural crest origin. Once collectively known as the ‘10% tumor’, based on the frequency of inherited forms of the disease, they are now referred to as the ‘10-gene tumor’, based on the number of susceptibility genes identified to date. Most familial cases of pheochromocytoma and/or paraganglioma and 10–20% sporadic cases carry germline mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, or MAX. The finding of somatic mutations in VHL and RET in an additional 10–15% of tumors has brought the proportion of all patients with PCC and/or PGL due to a genetic disruption in these genes to approximately one half. These findings impact on the clinical management of patients. The diversity in the genetic etiology has transcription correlates, which are reflected in the 2 main transcription signatures underlying these mutations: a pseudohypoxic cluster (VHL and SDH gene mutation carriers) and a cluster rich in kinase receptor signaling and protein translation pathways (RET, NF1, TMEM127 and MAX mutation carriers). Recognition of these clusters offers clues to better understand tumor pathogenesis as well as a rationale for the development of targeted therapies. In this report we provide an overview of the transcription-based classification of PCCs and PGLs, an update on the more recently identified susceptibility genes and an outline of current gaps in this research field as well as challenges for the coming years.Keywords
This publication has 40 references indexed in Scilit:
- Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemiaNature Medicine, 2011
- SDHA is a tumor suppressor gene causing paragangliomaHuman Molecular Genetics, 2010
- Germline mutations in TMEM127 confer susceptibility to pheochromocytomaNature Genetics, 2010
- Regulation of Gene Expression in Hepatic Cells by the Mammalian Target of Rapamycin (mTOR)PLOS ONE, 2010
- Pathogenicity of DNA Variants and Double Mutations in Multiple Endocrine Neoplasia Type 2 and Von Hippel-Lindau SyndromeJournal of Clinical Endocrinology & Metabolism, 2010
- The Warburg Effect Is Genetically Determined in Inherited PheochromocytomasPLOS ONE, 2009
- SDH5 , a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in ParagangliomaScience, 2009
- SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromesJournal of Internal Medicine, 2009
- Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1Proceedings of the National Academy of Sciences of the United States of America, 2008
- A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in PheochromocytomasPLoS Genetics, 2005