Wilms Genetics

"Children susceptible to Wilms' tumor are born with a constitutional DNA mutation in one allele of a gene. One copy of a presumed tumor suppressor gene mutation is inherited from one parent and results from a spontaneous mutation. Under these circumstances, a new genetic event such as deletion of inhibition of the paired allele of the gene would be needed for tumorigenesis to occur. This genetic presentation increases the likelihood of bilateral tumors and earlier age at onset as compared with sporadic cases, in which tumorigenesis requires two independent mutations. Two-event activation of a tumor suppressor gene occurs at two different genetic sites. The first allele is inactivated by mutation of the gene itself; the second allele is inactivated by loss of heterozygosity (a loss of chromosomal material).

Wilms' tumor occurring in children with aniridia, genitourinary abnormalities, and mental retardation is known as the WAGR syndrome. Wilms' tumor will develop in 30% of these children. The karyotypic analysis of these patients demonstrates a deletion of the short arm (the p arm) of one copy of chromosome 11 at the 11p13 locus. The syndrome actually encompasses a number of contiguous genes, including the aniridia gene PAX6 and the first Wilms' tumor suppressor gene, called WT1. In contrast to WAGR, children with the Denys-Drash syndrome with Wilms' tumor have only point mutations of the WT1 gene. These patients account for approximately 1% of all children with Wilms' tumor. In instances of unilateral Wilms' tumor, fewer than 15% will have mutations of the WT1 gene. This suggests that more than one genetic locus is involved in the development of Wilms' tumor.

Children with Beckwith-Wiedemann syndrome have the WT2 gene, characterized by a loss of DNA at the 11p15 locus. Much interest has been focused on insulin-like growth factor II, which resides in 11p15, because it is subject to genomic imprinting. An additional Wilms' tumor locus is seen on the long arm (the q arm) of chromosome 16 (16q). This occurs in approximately 20% of patients with Wilms' tumor. Some investigators have suggested that this is a statistically important adverse prognostic factor. These patients have a relapse rate 3 times higher and a mortality rate 12 times higher than Wilms' tumor patients without loss of heterozygosity. Twelve percent of Wilms' tumor patients have loss of heterozygosity at chromosome 1p, and they too have higher relapse and mortality rates. The involvement of genes at 11p13, 11p15, and 16q3 does not play a role in familial cases of Wilms' tumors where a detailed linkage analysis is required. Children with nephrogenic rests in their kidneys are at risk for mutational change and development of Wilms' tumor."