Mutations in the WTI tumor suppressor gene are known t o contribute t o the development of Wilms' tumor (WT) and associated gonadal abnormalities. WTI is expressed principally in the fetal kidney, developing gonads, and spleen and also in the mesothelium, which lines the coelomic cavities. These tissues develop from mesenchymal components that have subsequently become epithelialized, and it has therefore been proposed that WTI may play a role in this transition of cell types. To test the possible involvement of this gene in malignant mesothelioma, we have first studied its expression in a panel of human normal and malignant mesothelial cell lines. WTI mRNA expression levels varied greatly between the cell lines and no specific chromosomal aberration on I I p, which could be related t o the variation in WTI expression in these cell lines, was observed. Furthermore, no gross deletions, rearrangements, or functionally inactivating point mutations in the WTI coding region were identified. All four WTI splice variants were observed at similar levels in these cell lines. The WTI gene encodes a zinc-finger transcription factor and the four protein isoforms are each believed t o act as transcriptional repressors of certain growth factor genes. Lack of W7b expression is thus predicted t o result in growth stimulation of tumor cells. Binding of one particular WTI isoform construct to the insulin-like growth factor 2 (IGFZ) and platelet-derived growth factor A (PDGFA) gene promoters has been demonstrated t o result in repression of these genes in transient transfection studies. Analysis of IGF2 and PDGFA mRNA expression levels compared with WTI mRNA expression levels failed t o demonstrate an inverse correlation in the mesothelial cell lines, which endogenously express these genes. Finally, the putative role of WTI in the transition of cell types was investigated. No obvious correlation between WTI expression levels and cell morphology of the malignant mesothelial cell lines was evident from this study. Moreover, no change in WJI expression was observed in normal mesothelial cells which were, by alteration of culture conditions, manipulated t o switch from the mesenchymal to epithelial morphology. Genes Chromosom Cancer 12: 87-96 (1995).