TY - JOUR
T1 - An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes
AU - Gimenez-Roqueplo, A. P.
AU - Dahia, P. L.
AU - Robledo, M.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - MAX
KW - SDHB
KW - SDHD
KW - TMEM127
KW - VHL
KW - genetics
UR - http://www.scopus.com/inward/record.url?scp=84860834761&partnerID=8YFLogxK
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U2 - 10.1055/s-0031-1301302
DO - 10.1055/s-0031-1301302
M3 - Review article
C2 - 22328163
AN - SCOPUS:84860834761
SN - 0018-5043
VL - 44
SP - 328
EP - 333
JO - Hormone and Metabolic Research
JF - Hormone and Metabolic Research
IS - 5
ER -