Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas

Pheochromocytomas arise sporadically and as a component tumor of the inheri ted cancer syndromes von Hippel-Lindau disease (VHL), multiple endocrine ne oplasia 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 wa s conducted to examine a large series of 36 VHL-related pheochromocytomas f or somatic VHL and RET gene alterations and loss of heterozygosity (LOH) of markers on chromosome arms 1p, 3p, and 22q. For comparison, the same analy ses were performed in 17 sporadic pheochromocytomas. We found no somatic in tragenic mutations within VHL and RET in any VHL or sporadic pheochromocyto ma, and no pheochromocytoma demonstrated upstream VHL gene hypermethylation . Of interest, we found significantly different LOH frequencies at 3 loci b etween 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%, respectiv ely) in VHL pheochromocytomas argue for the importance of VHL gene dysregul ation and dysfunction in the pathogenesis of almost all VHL pheochromocytom as. In contrast, the relatively low frequency of 3p LOH (244; P much less t han 0.0001) and the lack of intragenic VHL alterations compared with the hi gh 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, esp ecially on Ip, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic vs. VHL pheochromocytoma gen esis are distinct.