title: New insights into the genetics of familial chromaffin cell tumors.
abstract: We review genetic aspects and recent advances in our understanding of the molecular pathogenesis of familial chromaffin cell tumors (pheochromocytoma, paraganglioma). About 10 percent of pheochromocytomas are familial and occur as part of multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1 (NF 1). A subset of paragangliomas, tumors that can also produce and secrete catecholamines, are also familial and occur in patients with germline mutations in genes that encode subunits of the mitochondrial complex II. The precise molecular mechanisms underlying the pathogenesis of chromaffin cell tumors remain widely unknown, although recent studies in hereditary tumors help elucidate their development. In MEN 2, overrepresentation of mutant RET in selected adrenomedullary cells may be an important mechanism in initiating the formation of a pheochromocytoma. In VHL disease, pheochromocytoma development appears to occur according to Knudson's two-hit model, a VHL germline mutation and wildtype allelic deletion. Tumorigenesis of NF1-associated pheochromocytomas remains unknown, as does tumor formation (i.e., carotid body tumor) in patients with germline mutations in SDHB, SDHC, and SDHD, genes that encode subunits of the mitochondrial complex II, the smallest complex in the respiratory chain. Many genetic alterations have been found in sporadic chromaffin cell tumors. However, at present such genetic changes are difficult to place into context with regard to tumor formation and progression.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. kochk@exchange.nih.gov
authors.forename: Christian A
authors.initials: CA
authors.lastname: Koch
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Frederieke M
authors.initials: FM
authors.lastname: Brouwers
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D004579:Electron Transport / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases