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e explained by assuming that the number of target-cells in mice is too low and therefore a
second mutation in the other allele never occurs.
Another mechanism of inactivation which could be involved in the pathogenesis of
Wilms' tumor is genomic imprinting, because in more than 90 percent of the tumors maternal
allelic loss is observed. This imprinting is probably restricted to the IIpl5 locus because this
preferential loss is not the wn gene on II p 13 (van Heyningen and Hastie, 1992; Koi et al.,
1993). The preferential loss of the maternal allele might indicate that the paternal allele is
imprinted, resulting in loss of expression of the susceptibility gene from this locus. Other
mechanisms which might explain this finding are that imprinting could somehow enhance the
rate of induction of small mutations in the paternal allele or protect for mutations in the
maternally derived gene during gametogenesis. The net result in all of these models is
inactivation of both maternal and paternal alleles as could be expected when the predisposing
gene is a tumor suppressor gene. However, other mechanisms might be the outcome of this
imprinting effect when we deal with an oncogene for instance. More details about this issue
are provided in a very recent review about genomic imprinting (Tycko, 1994).
The von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome in
which in addition to renal cell carcinoma, also hemangioblastomas of the central nervous
system and retina and pheochromocytomas occur. However, Wilms' tumors are never found.
Recently, the VHL gene on chromosome 3p25-p26 was isolated and both large
(nonoverlapping) deletions and small mutations were observed in YHL kind reds and sporadic
renal cell carcinomas (Latif et aI., 1993). The gene probably encodes a 284 amino acid
protein without any significant homology to already isolated genes in the databases.
However, an acidic tandemly repeated pentamer is observed in the putative protein, which
suggests a role in signal transduction or cell adhesion (Latif et aI., 1993).
3.5 The RET Pl'oto-oncogene
The RET proto-oncogene, located on chromosome 1 Oq 11. 2, was originally isolated because
the gene became activated by rearrangement during NIH3T3 cell transformation (Takahashi
et aI., 1985). Later, it also appeared to playa role in human cancer because in 25% of
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