Wilms tumor genes.

Multiple 'WT' genes exist. The WT1 gene at chromosomal band 11p13 has been cloned and is known to be important in the etiology of at least some tumors by virtue of the identification of both germline and somatic mutations in WT patients. Genes at 11p15 and 16q are also involved, either as initiating or tumor progression events. An unlocalized familial predisposition gene is also known to be important etiologically. The identification of several genes that are involved in the etiology or progression of WT, the preferential loss of maternally derived alleles in tumor tissue, and the observed reduction to 11p homozygosity in normal tissue DNA from some patients, all strikingly indicate that a simple, one-locus-'two-hit' genetic model for WT is inadequate. The question is not if this model needs to be modified, but how it should be modified, or if it is even valid enough to be a starting point for understanding the genetics of Wilms tumor. To begin to address this, several questions can be asked. Do all Wilms tumors carry mutations at the WT1 locus? Do both alleles at the WT1 locus need to be inactivated or lost for tumorigenesis? Or, instead, do some WT1 mutations act dominantly? Do patients with bilateral disease carry germline mutations as originally hypothesized, or, as more recently suggested, is bilateral disease the result of early somatic mutations, genomic imprinting, or multifactorial inheritance? Must mutations at an 11p15 locus and/or 11p15 LOH accompany WT1 mutations, or do 11p13 and 11p15 mutations act independently of each other? Have tumors from familial WT cases (who do not carry germline WT1 mutations) sustained somatic mutations at the WT1 locus, the 11p15 locus or the 16q locus? Conversely, do tumors from sporadic WT patients carry somatic mutations at the non-11p familial predisposition gene? Will most tumors be found to carry mutations at the same one or two loci, but differ only with regard to whether the mutations are somatic or germline? Are effects of genomic imprinting layered over, so to speak, a framework of classically mendelian mutations, or in some cases is imprinting the mechanism by which genes are inactivated or their normal function modulated? Although not definitive, there are data that bear on some of these questions. Germline mutations have been observed in patients with bilateral tumors, but may not prove to be a universal feature of bilateral disease.(ABSTRACT TRUNCATED AT 400 WORDS)