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found in association with the hereditary disorders WAGR, Denys-Dash and Beckwith­
Wiedemann. A combination of genetic mapping, karyotype and DNA analyses have resulted
in evidence supporting three distinct loci for Wilms' tumor, two on the short arm of
chromosome II (llpl3 and llp15) and one still unknown (Haber and Housman, 1992).
Apart from the involvement of the 11p15 locus in the development of Wilms' tumor, loss of
this region has been found in breast cancer, lung cancer and acute myelogenous leukemia
(Ali et aI., 1987; Henry et aI., 1989; Westonetal., 1989; Ahujaetal., 1990). However, the
llpl3 locus is probably involved in only a very limited number of tumor types.
In 1990 two independent groups were able to isolate the 11pl3 derived WTl gene,
using the positional cloning approach (Call et aI., 1990; Gessler et aI., 1990). This 345
amino acid protein has the hallmarks of a transcription factor (among others four zinc finger
domains). The binding of this protein to the EGR-1 and IGF-II promoter results in
transcriptional repression (Drummond et aI., 1992; Wang et aI., 1992). Most mutations, both
small mutations in the wrl transcript and (homozygous) deletions in the gene, resulted in
inactivation of the WTJ gene and some cases clearly support the recessive tumor suppressor
gene model (Haber et aI., 1990; Cowell et aI., 1991; Huffet aI., 1991; Ton et aI., 1991).
Not all tumors show mutations in (both alleles 01) this gene suggesting that at least some
altered WTl gene products can function in a 'dominant negative' way (Haber et aI., 1990)
or that in these cases another putative tumor suppressor loclis plays a role too. Evidence
exists that both 11p13 and 11pl510ci can playa role in a single tumor (Henry et aI., 1989).
Mutations in the WT-J gene are probably restricted to Wilms' tumors, as so far only a
somatic homozygous missense mutation in the ~vrl gene was found in a mesothelioma (Park
et aI., 1993). The following findings indicate an important role of WTl in urogenital
development. Denys-Drash syndrome is a rare human developmental disorder of the genitourinary
system characterized by pseudohermaphroditism, renal failure and predisposition to
Wilms' tumor. This syndrome is caused by specific point mutations in the zinc finger domain
of the WTl protein or other mutations involving this domain (Pelletier et aI., 1991; Little
et aI., 1993). The expression of the WTl gene is limited to certain organs including the
genitourinary tract (Pritchard-Jones et aI., 1990). This probably explains the limited
occurrence of "WI'1 mutations in cancers other than Wilms'tumor. In addition, murine WTl
homozygous knock out mice are lethal with failure of kidney and gonad development
(Kreidberg et aI., 1993). The heterozygous mice did not develop Wilms' tUIllOr. This might
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