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  1. Renal carcinoma appears in both a sporadic and a hereditary form. Eighty-five percent of sporadic renal carcinomas are of the clear cell histologic type, 5 to 10 percent are papillary renal carcinoma, and the remainder are less common histologic types such as chromophobe and collecting-duct renal carcinomas.

  2. The most well characterized form of hereditary renal carcinoma is von Hippel-Lindau (VHL). VHL is a hereditary cancer syndrome in which affected individuals are at risk to develop tumors in a number of organs, including the kidneys, cerebellum, spine, eye, inner ear, adrenal gland, and pancreas. VHL families are categorized as VHL type I (without pheochromocytoma) or VHL type II (with pheochromocytoma).

  3. The VHL gene, which has the characteristics of a tumor-suppressor gene, has been identified on the short arm of chromosome 3. The VHL gene has three exons and encodes a protein of 213 amino acids. Both copies of the VHL gene are inactivated in tumors in VHL patients—mutation in the inherited allele and loss of the wild-type allele. VHL gene mutation analysis provides a method for early diagnosis of VHL in asymptomatic individuals or in clinical situations such as hereditary pheochromocytoma where the diagnosis is in doubt. Since VHL manifestations often occur in childhood, testing early in life is recommended so that appropriate intervention can be instituted. There is a marked genotype/phenotype correlation with VHL gene mutation and the manifestation of the VHL; VHL type II families are characterized by missense mutations of the VHL gene. There is a “hot spot” for VHL type II at a single codon in the 5′ end of exon 3 of the VHL gene.

  4. Inactivation of both copies of the VHL gene is an early event in clear cell renal carcinoma, where a high percentage of VHL gene mutations and loss of heterozygosity (LOH) have been detected. VHL gene mutations including nucleotide insertions, deletions, substitutions, and nonsense mutations have been found in each of the three exons. Neither VHL gene mutation nor VHL LOH is found in papillary renal carcinoma. A molecular genetic classification of renal carcinoma, clear cell versus papillary, has been proposed, with clear cell renal carcinoma characterized by VHL gene mutation. VHL gene mutations have been detected in DNA extracted from formalin-fixed material and tissue aspirates, providing a potentially useful diagnostic tool. Somatic VHL gene mutations have been detected in sporadic tumors from other organs affected in VHL, including cerebellar hemangioblastoma and epididymal cystadenoma. With the exception of rare reports, VHL is not mutated or implicated in other sporadic cancers.

  5. The VHL suppressor gene product has begun to be characterized. VHL forms a stable tetramolecular complex with two subunits of the highly conserved heterotrimeric transcription elongation factor elongin (SIII) and an additional protein called Cul-2. Elongin is composed of three subunits: A, B and C. Elongin A is required to inhibit processing of RNA pol II, allowing cell processivity of transcription. Elongin B enhances the assembly of elongin C to either elongin A or VHL. VHL and elongin A compete for binding to B and C via a short shared sequence motif. This sequence, found in the third exon of VHL, is highly mutated in both VHL and sporadic renal cell carcinoma (RCC), and these loss-of-function VHL mutations are associated with loss of assembly of VHL with the B and C subunits. While VHL can competitively inhibit the assembly of a functional ABC transcription elongation factor, it is not clear that transcription elongation inhibition is the mode of action of VHL. These proteins combine to target other proteins for ubiquitin-mediated degradation, and this observation may provide the best current hint of the biochemical function of the VHL complex. Cul-2, the fourth known component of the VHL complex, is a member of the Cdc53 family of proteins. The VHL-Cul-2 association depends on the integrity of the VHL-elongin B/C heterotrimeric complex. Cul-2 is a cytosolic protein that can be translocated to the nucleus by the VHL protein. The VHL protein has been found both in the nucleus and the cytosol of transiently transfected cells. There is a tightly regulated, cell density-dependent transport of VHL into and/or out of the nucleus. In densely grown cells, the VHL signal is predominantly in the cytoplasm, whereas in sparse cultures, most of the signal is detected in the nucleus. Immunofluorescence studies of mutant VHL protein revealed that the C-terminal region of the VHL protein is required for localization to or retention in the cytosol. In exon 1 deletion mutants, the protein remains predominantly in the cytosol under both sparse and confluent conditions. The VHL protein is required for cell cycle exit on serum withdrawal. RCC cells (VHL −/−) fail to exit the cell cycle on serum withdrawal. Reintroduction of the wild-type VHL gene restores the ability of the VHL −/− RCC cells to exit the cell cycle. The cyclin-dependent kinase inhibitor p27 has been shown to accumulate on serum withdrawal in the presence of VHL. This is associated with stabilization of the p27 protein.

  6. Sporadic clear cell renal carcinomas are characterized by a high degree of neoangiogenesis; angiogenesis is also a striking feature in the clinical manifestations of VHL. Both clear cell renal carcinoma and cerebellar hemangioblastoma are characterized by a marked elevation in expression of vascular endothelial growth factor (VEGF). The increased expression of VEGF is reversed in renal carcinoma cells by reintroduction of the wild-type VHL gene. This reversal is blocked by either anoxia or low serum conditions, suggesting that VHL may play a role in the normal regulated induction of angiogenesis. This critical gene is one of the first identified targets of VHL function.

  7. Hereditary papillary renal cell carcinoma (HPRC) is a hereditary cancer syndrome in which affected individuals are at risk to develop bilateral, multifocal papillary renal cell carcinoma. This syndrome, which has an autosomal dominant inheritance pattern, is caused by missense mutations in the tyrosine kinase domain of the MET proto-oncogene.

  8. Familial renal oncocytoma is characterized by a predisposition to develop bilateral, multiple renal oncocytomas in affected family members.

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