WT1 splicing alterations in Wilms' tumors.

Hereditary and sporadic forms of tumors are generally related to germ-line and somatic mutations of the same tumor suppressor gene. Unexpectedly, in Wilms' tumor, somatic mutations of the WT1 gene were found only occasionally in sporadic cases, although constitutional mutations of this gene are clearly associated with predisposition. It has been suggested that abnormal splicing may be another mode of somatic WT1 alteration. However, this idea was based on the analysis of a small series of tumors, precluding accurate evaluation of the frequency of such changes. To investigate WT1 changes at the somatic level in more detail, we analyzed the levels of the four isoform transcripts produced by alternative splicing events in a large series of 50 tumors, normal mature kidneys, and fetal kidneys. We characterized splicing alterations in 63% of sporadic Wilms' tumors. Moreover, taking into account the decreased and increased overall levels of WT1 mRNA, the percentage of sporadic tumors with changes in WT1 expression reached 90%. Whether and how these alterations of expression play a role in the tumorigenic process remain to be evaluated.