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

Abstract

Summary Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found. (2000) 83(2), 177-183 © 2000 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1283, available online at http://www.idealibrary.com on Three markers were used to evaluate linkage to WT1. The marker order determined from LDB (Collins et al, 1996) is centromere-D11S904-2.5 cM-D11S4154-3.5 cM-D11S907-telomere. WT1 is located between D11S4154 and D11S907. At least six markers were used to evaluate linkage to FWT1. Additional markers were analysed to generate informative data when required. The marker order determined from LDB is centromere-D17S946/D17S250-2.5 cM-THRA1-1 cM-D17S8001 cM-D17S579-2.0 cM-D17S806-4 cM-D17S588-2 cM-D17S1820-telomere. At least six markers were examined to determine linkage to FWT2. The marker ordered determined from Genethon marker map (Dib et al, 1996) is centromere-D19S571-4 cM-D19S921-2.0 cM-D19S572-1.0 cM-D19S924-3.0 cM-D17S254/D19S418-3.0 cM-D19S926-1.0 cM-D19S891-telomere. Statistical analysisGenetic linkage analysis was performed using the FASTLINK program (Cottingham et al, 1993). Familial WT was modelled as a rare dominant (q = 0.000001) with a penetrance of 30% (Rahman et al, 1996). Allele frequencies were calculated from 15 unrelated individuals. Multipoint LOD scores were generated using two informative markers from each chromosome haplotype. When analysing family HPN12 the marriage loop was broken at ID1460, using the makeped component of the LINKAGE package. RESULTSOf 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. 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). These two families were included in the current study. Six previously unpublished families were also included. Three of these (WILMS 12, WILMS 13 and HPN12) also show evidence against linkage to FWT1 and WT1, and are illustrated in Figures 1B, C and E respectively. The remaining new families F2655 (uncle and nephew affected), F1124 (affected sib pair) and MON 948 (affected sib pair) were linked at either/both FWT1 and WT1 and are not shown. Therefore, five of our total series of 19 families, WILMS 7, FAMILY M, WILMS 12, WILMS 13 and HPN12 are highly unlikely to be due to either WT1 or FWT...

The Role of BRCA1 and BRCA2 Genes in the Appearance of Pediatric and Adolescent Disorders

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Familial extrarenal Wilms tumor

“…Genotyping of WT1, FWT1, and FWT2 loci were performed using polymorphic microsatellite markers [10]. Three markers were used for WT1 linkage analysis: D11S904, D11S4154, and D11S907.…”

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“…Only 1-2% of Wilms tumor cases cluster within families, but the underlying causes of these rare pedigrees are heterogeneous and complex. Furthermore, several families not linked to WT1, FWT1, or FWT2 exist, indicating further genetic heterogeneity in familial Wilms tumor [3]. Cochran and Froggatt reported one instance of consanguinity associated with a familial occurrence of Wilms tumor [4].…”