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Differential Genetic Alterations in von Hippel-Lindau Syndrome-Associated and Sporadic Pheochromocytomas¹

Department of Internal Medicine, Division of Nephrology and Hypertension (B.U.B., M.G., S.G., B.M., H.P.H.N.), and Department of Surgery (G.K.), Albert Ludwigs University of Freiburg, 79106 Freiburg, Germany; Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center (C.E.), Columbus, Ohio 43210; and Clinical Research Center Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Bernhard Bender, Medizinische Universitätsklinik, Hugstetterstrasse 55, 79106 Freiburg, Germany. E-mail: bender{at}med1.ukl.uni-freiburg.de

Pheochromocytomas arise sporadically and as a component tumor of the inherited cancer syndromes von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), and type 1 neurofibromatosis. Germline mutations of the VHL tumor suppressor gene (VHL) are responsible for VHL, and germline RET protooncogene mutations are associated with MEN 2. The present study was conducted to examine a large series of 36 VHL-related pheochromocytomas for somatic VHL and RET gene alterations and loss of heterozygosity (LOH) of markers on chromosome arms 1p, 3p, and 22q. For comparison, the same analyses were performed in 17 sporadic pheochromocytomas. We found no somatic intragenic mutations within VHL and RET in any VHL or sporadic pheochromocytoma, and no pheochromocytoma demonstrated upstream VHL gene hypermethylation. Of interest, we found significantly different LOH frequencies at 3 loci between sporadic and VHL tumors; the more than 91% LOH of markers on 3p and the relatively low frequencies of LOH at 1p and 22q (15% and 21%, respectively) in VHL pheochromocytomas argue for the importance of VHL gene dysregulation and dysfunction in the pathogenesis of almost all VHL pheochromocytomas. In contrast, the relatively low frequency of 3p LOH (24%; P << 0.0001) and the lack of intragenic VHL alterations compared with the high frequency of 1p LOH (71%; P = 0.0003) and the moderate frequency of 22q LOH (53%) in sporadic pheochromocytomas argue for genes other than VHL, especially on 1p, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic vs. VHL pheochromocytoma genesis are distinct.

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