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

Abstract

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.

The N131S Mutation in the von Hippel-Lindau Gene in a Japanese Family with Pheochromocytoma and Hemangioblastomas

“…showed that the LOH at 3p was detected in 91% PHE with VHLD; this value was relatively high when compared with 24% incidence observed with the LOH at 3p in sporadic PHE [24]. This is in agreement with the result of our present study.…”

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

“…VHL is considered a classical tumor suppressor gene in the sense that, in accordance with Knudsons two-hit model, biallelic inactivation is usually required for tumorigenesis (Knudson 1971(Knudson , 1996. Loss of heterozygosity (LOH) of the wild-type allele is frequent in VHL-associated tumors, including PCCs (Crossey et al 1994), and hypermethylation of the wild-type allele as an alternative mechanism of gene inactivation has also been reported (Herman et al 1994, Prowse et al 1997, although not in PCCs (Bender et al 2000). Disease-causing mutations in VHL can be missense, nonsense, as well as deletions and insertions (indels), with missense mutations being more frequent in families with PCC/PGL (Woodward & Maher 2006).…”

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

“…Loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies performed by us and others have reported allelic losses at 1p, 3pq, 17p, and 22q, but corresponding genes have not been identified. [3][4][5][6] Particularly 17p, the chromosome arm where the p53 gene is located, is interesting to investigate knowing that aberrations in this gene are implicated in many inherited and sporadic forms of malignancy, such as colon, lung, brain, and breast tumors. 7 p53 is functionally involved in guarding the stability of the genome.…”