VHL demonstrates an autosomal dominant pattern of inheritance; a parent who carries the VHL gene will have offspring with a 50% chance of also having the VHL gene. Some families have fewer than 50% affected offspring and some parents of affected offspring do not manifest VHL even though based on their family history they are "obligate carriers" (22). This has been explained by incomplete penetrance; the gene is inherited but not expressed (1). However, it appears that many of these cases represent asymptomatic carriers and if they are carefully screened will be found to have VHL (1,4). Nevertheless, rarely VHL can arise without a family history. Such new mutations occur in only 1-3% of cases (3,23).
The VHL gene is the archetype of a tumor suppressor gene; a gene whose normal function is to regulate cell growth. When both copies of the gene are inactivated by mutation or loss, cell growth is unchecked and tumors result. Each patient with VHL inherits the germ line mutation from their affected parent but also one, normal (wild type) copy of the gene from their other parent. Knudson advanced a "two hit hypothesis" to explain tumorigenesis in such conditions (Figure 2).
Figure 2. The two mutation theory of tumor suppression genes originally
proposed by Knudson. Each cell contains pairs of chromosomes. Solid circles
are sites of mutations. The first mutation is usually a structural change
in a specific cancer gene (single solid circle). The second mutation usually
involves a much larger region of the chromosome (multiple solid circles).
Both copies of the gene must be lost for cancer to develop. (reprinted with
permission from Zbar B: Chromosomal deletions in lung cancer and renal cancer.
In: Rosenberg SA, DeVita VT Jr., Hellman S eds. Important advances in Oncology.
Philadelphia, JB Lippincott 1989 p41-60)
Knudson suggested that the germ line mutation is present in all cells but only those cells in susceptible target organs that undergo a second mutation of wild type allele develop tumors (24,25). Knudson demonstrated how this model explained why children with hereditary retinoblastomas and Wilms tumors developed multifocal tumors at a younger age, than children with sporadic tumors. Empiric observation of renal cancer in VHL suggests a similar model is at work (26). The susceptible target organs in VHL can be grouped as cerebellar and retina cells (resulting in hemangioblastomas), neural crest cells (resulting in pheochromocytomas, paraganglioma and possibly islet cell tumors) and glandular viscera (resulting in renal, pancreatic, epididymal and endolymphatic sac tumors) (Figure 3).
Figure 3. Schematic of susceptible tissues in VHL. After the "2nd
Hit" is incurred (See Figure 2) tumors develop in specific tissue types.
The cerebellum, spinal cord, retina, and selected supratentorial sites are
susceptible to the development of hemangioblastomas. Peripheral neural crest
tissue is susceptible to the development of pheochromocytomas, paragangliomas
and possibly islet cell tumors. The kidneys, pancreas, epididymis and endolymphatic
sac form another group of susceptible tissues.
There is no evidence that an additional site of genetic abnormality (genetic heterogeneity) exists, although additional "promotor" genes may be operant (27). The loss of tumor suppressor genes is one of the most fundamental mechanisms of tumorigenesis and has been implicated in a number of human cancers in both their sporadic and hereditary forms (28,29).
The short arm of chromosome 3 was implicated in the genetics of VHL by the observation that patients with familial renal cancer had chromosomal translocations involving this chromosome (14,15,30). The study of various tumors from patients with VHL revealed loss of segments of DNA on the short arm of chromosome 3, (3p designates the short arm of chromosome 3) (14,30,31). This loss of DNA occurred on the allele from the non-affected parent and represented the second of two hits needed to form the tumor. DNA probes were then used to identify nucleotide fragments that were coinherited with the disease in affected family members. Ultimately, several "flanking markers", DNA probes that were located proximal and distal to the purported gene, were discovered at the 3p25-26 locus (27,32). These probes are now used clinically to identify asymptomatic family members with VHL. Further work revealed a segment of DNA within the 3p25-26 locus that was consistently transmitted with the disease; this constitutes the "VHL gene" and the major portion of the nucleotide sequence was determined (3) (Figure 4).
Figure 4. Distribution of mutations in the VHL gene. Each box represents
a cloned exon. Arrows pointing up indicate the sites of nucleotide substitutions;
arrows pointing down indicate sites of nucleotide insertions. Vertical lines
within the exons indicate sites of nucleotide deletions and * represent
"nonsense" mutations. Note that although there are many different
specific mutations they tend to cluster at certain "hot spots"
on the gene. (modified and reprinted with permission from Chen F, Kishida
T, Yao M, et al. Germ line mutations in the von Hippel Lindau disease tumor
suppressor gene: correlation with phenotype. Human Genetics (in press).
Currently, the precise mutations within the gene are being defined. There may be "hot spots" or fragile sites within the gene associated with particular tumors such as renal carcinoma (29). Radiologic imaging played a major role in the process by identifying asymptomatic carriers with VHL and thus allowing more statistically powerful conclusions to be drawn about the various DNA markers.
The discovery of flanking markers and specific genetic mutations means that asymptomatic family members can often be screened for VHL with a blood test and that patients who have already been screened with imaging tests and have non-specific findings such as renal cysts or epididymal cysts can be confirmed or ruled out as having VHL. However, the exact mutation has not yet been identified in up to 20% of VHL patients. Moreover, blood testing does not yet allow every individual without a family history of VHL to be tested. A minimum of two affected family members are needed for the DNA markers to be useful in linkage analysis and presently up to 14% of families will be "uninformative" with respect to these DNA markers (27). Recombination, the exchanging of one segment of the allele for the homologous contralateral segment occurs with a 1% frequency at this locus and will produce a false negative result (27). Thus, patients with negative genetic tests should still be periodically tested for the major complications of VHL. Individuals from families with a specific known genetic mutation, can be tested directly by analyzing their DNA for the family's mutation.
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