Chapter 38

## Abstract

1. Wilms tumor is a pediatric kidney cancer that can arise sporadically or in children with congenital syndromes conferring genetic susceptibility. In addition, some 10 percent of children with Wilms tumor present with bilateral cancers, evidence of a predisposing genetic lesion.

2. The genetic loci associated with the development of Wilms tumor have been identified by analysis of gross karyotype abnormalities in children with Wilms-associated syndromes, as well as by molecular analyses of DNA losses in tumor specimens. A genetic locus on chromosome 11 band p13 has been linked to Wilms tumor arising in the context of aniridia and abnormalities of genitourinary development (e.g., WAGR syndrome). A second locus on chromosome 11 band p15 is associated with hemihypertrophy (e.g., Beckwith-Wiedemann syndrome) and predisposition to Wilms tumor and other pediatric neoplasms. A third Wilms locus has been mapped recently to chromosome 17q12-21.

3. The WT1 gene, mapping within the 11p13 genetic locus, was isolated in 1990. It encodes a transcription factor whose expression is strictly developmentally regulated in the normal kidney. Like the fetal kidney cells from which they appear to originate, most Wilms tumors express high levels of WT1 protein. However, in a fraction of Wilms tumors, WT1 is either deleted or mutated to an inactive form, consistent with its characterization as a tumor suppressor gene. Reintroduction of wild-type WT1 into a Wilms tumor cell line with an aberrant endogenous WT1 transcript results in inhibition of cell growth.

4. Inactivation of WT1 in one germ-line allele confers a high degree of susceptibility to Wilms tumor, which is triggered by loss of the second WT1 allele in somatic tissues. Hemizygosity for WT1 in the germ line also results in a variable degree of developmental abnormalities in the genitourinary tract, more prominent in males than in females. Moreover, specific point mutations within the DNA-binding domain of WT1 result in a dominant negative phenotype, characterized by severe abnormalities in sexual and renal development (Denys-Drash syndrome). In the mouse, hemizygous inactivation of WT1 is not associated with genitourinary defects or tumor predisposition. However, homozygous inactivation of WT1 leads to failure of renal and gonadal development, as well as to malformations of the heart and diaphragm.

5. The protein encoded by WT1 belongs to a class of zinc-binding transcription factors, with multiple variants produced by alternative splicing. The four zinc-finger domains of WT1 recognize GC-rich DNA target sequences, an effect that is modulated by the variable insertion of three amino acids (KTS) between zinc fingers 3 and 4. WT1 appears to function as a transcriptional repressor, although physiologically relevant target genes remain to be defined. Potential protein interactors include another tumor suppressor gene product, p53, whose function is modulated by WT1. Inducible expression of WT1 in tissue culture cells triggers apoptosis, associated with repression of the epidermal growth factor receptor and induction of the cyclin-dependent kinase inhibitor p21. Dimerization of WT1 may contribute to the dominant negative phenotype displayed by mutants with a disrupted DNA-binding domain. Characterization of the normal pathways involved in WT1 function and of any potential interactions with other Wilms tumor genes may lead to a better understanding of normal kidney development and tumorigenesis.

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