Confirmation of FWT1 as a Wilms’ tumour susceptibility gene and phenotypic characteristics of Wilms’ tumour attributable to FWT1

Abstract

A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT.

Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1

“…Wnts 4, 5B, 7B and 11 are all expressed during kidney development, but of these only Wnt11 can result in transformation (Christiansen et al, 1996) and b-catenin accumulation (Ku and Melton, 1993). Curiously, human Wnt3 and Wnt15 have both been mapped to within 125 kb on human chromosome 17q21 (Bergstein et al, 1997), a region identi®ed as a familial Wilms' tumour gene, FWT1 (Rahman et al, 1998), although their expression in kidney has not been investigated. Wnt3 does appear to signal via the b-catenin pathway and result in transformation (Shimizu et al, 1997).…”

Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

“…Of 13 previously published families with two or more cases of WT, two families (WILMS 7 ( Figure 1A) and FAMILY M ( Figure 1D) are highly unlikely to be due to either FWT1 or WT1 mutations (Rahman et al, 1998). Both families are unlinked at FWT1.…”

“…Both families are unlinked at FWT1. WILMS 7 is unlinked at WT1 (Rahman et al, 1998). FAMILY M generates a small positive LOD score of 0.3 at WT1 (Table 1), but mutational screening by a combination of single strand conformation polymorphism and direct sequencing did not detect a predisposing WT1 mutation in this family (Baird et al, 1994).…”

“…The existence of this locus has been confirmed by analysis of additional affected members from MON 480 and a second unrelated pedigree (K1104) with seven cases of WT (Rahman et al, 1998). WT cases in FWT1-linked pedigrees tend to be diagnosed at a later age than non-familial cases (Rahman et al, 1998) and analyses of WT from MON 480 have demonstrated that loss of the wild-type FWT1 allele, inherited from the non-mutation carrying parent, does not occur (Rahman et al, 1997).…”

“…In all but one (Kaplinsky et al, 1996), the WT1 mutation was associated with congenital malformations, either urogenital abnormalities in males and/or aniridia. WT1 has been excluded as the susceptibility gene in several WT families in which no congenital abnormalities were observed (Grundy et al, 1998;Huff et al, 1988;Schwartz et al, 1991;Baird et al, 1994).…”