Two molecular subgroups of Wilms' tumors with or without WT1 mutations.

PURPOSE Wilms' tumors (WTs) exhibit more than one pattern of differentiation, each of which is associated with distinctive clinical features and treatment responses. Mutations in the WT1 gene are found predominantly in WTs with stromal histology. To better understand the biological and clinical features in different WTs, we have analyzed WTs with and without WT1 mutations for a set of parameters. EXPERIMENTAL DESIGN Twenty-two new WTs were analyzed for WT1 mutations by PCR single-strand conformational polymorphism. Five tumors with WT1 mutations and six tumors without WT1 mutations were studied for the presence of WT1 transcripts and protein as well as for the expression of differentiation markers. RESULTS Two new WT1 mutations were identified in stromal-predominant tumors, and none were identified in the other histological subtypes. Tumors with WT1 mutations expressed mutant messages, cytoplasmic truncated WT1 proteins, and muscle markers. In contrast, blastemal-predominant tumors without mutations showed nuclear WT1 protein staining. Both tumor types were positive for markers of early-induced mesenchyme and one marker of uninduced mesenchyme, but blastemal-predominant tumors also expressed cytokeratin, suggesting that these are further along the epithelial differentiation pathway. CONCLUSIONS Our data show that the two-hit inactivation of WT1 is operative in stromal-predominant WTs. Cells without functional nuclear WT1 protein start a faulty differentiation program. In contrast, blastemal-predominant tumors express wild-type WT1 and show early signs of epithelialization. The extensive rhabdomyomatous differentiation and the presence of WT1 mutations may be used as a diagnostic tool to identify a tumor subtype that seems to respond poorly to chemotherapy. These studies provide a foundation for improvement in tumor classification and ultimately for the development of more individualized tumor treatments.