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  • 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.

  • 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).

  • 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.

  • 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.

  • 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 ...

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