Genome-wide loss of heterozygosity analysis of WT1-wild-type and WT1-mutant Wilms tumors.

Wilms tumor (WT) is genetically heterogeneous, and the one known WT gene, WT1 at 11p13, is altered in only a subset of WTs. Previous loss of heterozygosity (LOH) analyses have revealed the existence of additional putative WT genes at 11p15, 16q, and 1p, but these analyses examined only one or a handful of chromosomes or looked at LOH at only a few markers per chromosome. We conducted a genome-wide scan for LOH in WT by using 420 markers spaced at an average of 10 cM throughout the genome and analyzed the data for two genetically defined subsets of WTs: those with mutations in WT1 and those with no detectable WT1 alteration. Our findings indicated that the incidence of LOH throughout the genome was significantly lower in our group of WTs with WT1 mutations. In WT1-wild-type tumors, we observed the expected LOH at 11p, 16q, and 1p, and, in addition, we localized a previously unobserved region of LOH at 9q. Using additional 9q markers within this region of interest, we sublocalized the region of 9q LOH to the 12.2 Mb between D9S283 and a simple tandem repeat in BAC RP11-177I8, a region containing several potential tumor-suppressor genes. As a result, we have established for the first time that WT1-mutant and WT1-wild-type WTs differ significantly in their patterns of LOH throughout the genome, suggesting that the genomic regions showing LOH in WT1-wild-type tumors harbor genes whose expression is regulated by the pleiotropic effects of WT1. Our results implicate 9q22.2-q31.1 as a region containing such a gene.