Horm Metab Res 2012; 44(05): 328-333
DOI: 10.1055/s-0031-1301302
© Georg Thieme Verlag KG Stuttgart · New York

An Update on the Genetics of Paraganglioma, Pheochromocytoma, and Associated Hereditary Syndromes

A.-P. Gimenez-Roqueplo
1  Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
2  INSERM, UMR970, Paris Cardiovascular Research Center, Paris, France
3  Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
P. L. Dahia
4  Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio (UTHSCSA), Texas, USA
5  Cancer Therapy and Research Center, UTHSCSA, Texas, USA
M. Robledo
6  Centro Nacional de Investigaciones Oncológicas (CNIO), Hereditary Endocrine Cancer Group, Madrid, Spain
7  Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain
› Author Affiliations
Further Information

Publication History

received 21 October 2011

accepted 22 December 2011

Publication Date:
10 February 2012 (online)


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.