Wilms tumor genetics

Abstract

Wilms tumor (WT), a sporadic and familial childhood kidney tumor, is genetically heterogeneous. One WT gene, WT1 at 11p13, has been cloned, but only a minority of WTs carry detectable mutations at that locus. WT1 can also be excluded as the predisposition gene in most WT families, implying the existence of other WT genes. Studies of WT families have demonstrated that familial predisposition is also heterogeneous and involves at least two other loci besides WT1. In addition to WT1 and the familial predisposition genes, a role for other genes in the development of WTs is implied by the somatic occurrence of genetic and epigenetic alterations such as loss of heterozygosity and loss of imprinting in tumors and, rarely, the observation of nonchromosome-11 constitutional aberrations in WT patients. Determining the pattern of presence or absence of these various genetic alterations in tumors and elucidating the function of the genes involved will provide a better understanding of the cellular processes that are critical for normal cell growth and differentiation, but are abrogated in the course of tumorigenesis.

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

“…Previous WT1 mutational analysis indicated that 15 of these 31 tumors carried germline or somatic mutations in WT1 (Huff, 1998). All mutations are predicted to inactivate WT1 function.…”

“…The genetic etiology of WT is heterogeneous, and several genes hypothesized to play a role in tumor development have been localized (reviewed in Huff, 1998). The only Wilmstumor gene identified to date, WT1 on chromosome 11p13 is vital for normal genitourinary development (Call et al, 1990;Gessler et al, 1990;Kreidberg et al, 1993).…”

“…The only Wilmstumor gene identified to date, WT1 on chromosome 11p13 is vital for normal genitourinary development (Call et al, 1990;Gessler et al, 1990;Kreidberg et al, 1993). Mutations that inactivate WT1 function are observed in about 5-20% of Wilmstumors (Gessler et al, 1994;Varanasi et al, 1994;Huff, 1998).…”

Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours

“…Chromosomal region 11p13 was first identified as a Wilms' tumour locus, WT1, because the region was found to be deleted in Wilms' tumours (Kaneko et al, 1981;Huff, 1998;Dome and Coppes, 2002, OMIM 194070). The Wilms tumour 1 (WT1) gene, isolated from the WT1 locus, was the first causative gene for Wilms' tumour (Call et al, 1990;Gessler et al, 1990).…”

“…The Wilms tumour 1 (WT1) gene, isolated from the WT1 locus, was the first causative gene for Wilms' tumour (Call et al, 1990;Gessler et al, 1990). However, WT1 aberrations, such as deletions and point mutations, are observed in only approximately 10 -20% of Wilms' tumours (Huff, 1998;Nakadate et al, 2001). The small number of WT1 mutations in Wilms' tumours suggests that WT1 can be inactivated by alterations that would not be detected by mutational analysis (Huff, 1998).…”