Vonhippellindau Syndrome And Renal Carcinoma

Von-Hippel-Lindau (VHL) syndrome is inherited in an autosomal-dominant fashion, with high penetrance, but variability in its phenotype. The most distinctive lesions in this multi-organ syndrome are angiomas and hemangioblastomas in the retina and cerebellum, respectively. Frequently, the patients also develop adenomas and cysts of the pancreas, epididymis, and the kidneys. All these tumors are benign, but «30% of VHL patients develop RCC, which can be bilateral and multifocal. It is always of the clear-cell type. A subtype of VHL disease now designated 'type II' is distinguished by an enhanced risk of pheochromocytoma, a tumor originating from the adrenal medulla and retaining the ability to produce catecholamines. Uncontrolled secretion of adrenalin and noradrenalin by pheochromocytomas causes increased blood pressure and metabolic disturbances which can be life-threatening.

Although a considerably variety of tumors can develop in von-Hippel-Lindau

Figure 15.5 The VHL gene and its products The VHL gene gives rise to two (A, B) major mRNAs and proteins by differential splicing.

syndrome, they share characteristic common properties, i.e. strong vascularization and the emergence of a clear cell component characterized by an increased rate of glycolytic metabolism and enhanced storage of glycogen and lipids. These are evidently properties observed in clear-cell renal carcinoma in general, i.e. also in sporadic cases.

The von-Hippel-Lindau syndrome is caused by germ-line mutations in a gene located at 3p25, appropriately designated VHL. It behaves like a classical tumor suppressor gene (^5.1). Thus, each individual tumor arising in the VHL syndrome has lost the function of the second VHL allele as well, either by mutation, promoter hypermethylation, recombination or, typical of clear-cell RCC, 3p deletion.

The VHL gene encodes in three exons 6.0 and 6.5 kb transcripts containing a much smaller coding region which is translated predominantly into a 213 amino acid protein (Figure 15.5). Shorter protein variants are formed through use of an alternative start codon and alternative splicing of exon 2.

The VHL protein forms an essential part of the substrate recognition module of a specific E3 ubiquitin ligase protein complex (Figure 15.6). Further members of the complex are Elongin B and Elongin C, Cullin 2, and RBX1, which binds the E2-ubiquitin component. There are several different E3 complexes in a cell, each specific for a different range of substrates. While all have a similar basic composition, their individual components vary, most decisively the substrate recognition module, after which they are therefore (usually) named.

The VHL E3 protein complex is by far not the only ubiquitin ligase important in human cancer (Table 15.4). The SCF-pTRCP E3 complex directs the breakdown of 0-Catenin. Its failure is crucial in colon carcinoma (^13.2) and in many liver cancers (16.2). The proto-oncogene product HDM2 constitutes the recognition protein of the

Figure 15.6 The VHL ubiquitin ligase complex See text for further explanations.

Most frequent location of mutations

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