Imbalanced expression of functionally different WT1 isoforms may contribute to sporadic unilateral Wilms' tumor

Functional loss of the product of the Wilm's tumor suppressor gene (wt1) has been identified in subsets of familial Wilms' tumors. Previously, four alternative splice products of WT1 were recognized and each was found to regulate transcription of effector genes differently, suggesting that disruption of the normal ratio of these spliced products will disrupt the normal expression patterns of WT1 effector genes and perhaps lead to Wilms' tumor. In support of these suggestions, we found that four of seven cases of sporadic unilateral Wilms' tumor had striking differences in the ratios of the spliced products of WT1 compared with each other and normal kidney. These data indicate that in addition to structural mutations, alterations in the relative amounts of the mature WT1 isoforms may also be important in the etiology of sporadic Wilms' tumor.