A RODENT MODEL FOR WILMS-TUMORS - EMBRYONAL KIDNEY NEOPLASMS INDUCED BY N-NITROSO-N'-METHYLUREA

Embryonal kidney cell tumors develop in rats given the alkylating agen t N-nitroso-N'-methylurea as neonates. These tumors resemble the child hood Wilms tumors in their histopathology. Deletions and mutations in the Wilms tumor suppressor gene, WT1, are present in up to 6% of child hood nephroblastomas. To investigate the role of WT1 in rat kidney tum origenesis, we studied the genetic alterations in WT1 and its target g enes. Point mutations were found in WT1 cDNA in 7 of 18 kidney tumors. Mesenchymal tumors contained G --> A transition mutations in codons 1 28, 364, and 372, typical of the methylating action of N-nitroso-N'met hylurea on DNA. Each of the four nephroblastomas contained the same T --> A mutation at codon 111 of WT1, reflective of transversion mutagen esis by N-nitroso-N'methylurea in vivo. Like Wilms tumors, mRNA levels of WT1, IGF2, Pax-2, and MK genes were higher than newborn kidney in the majority of the tumors. The histopathology of the rat kidney tumor s and the genetic alterations are reminiscent of those observed in Wil ms tumors, establishing this as a relevant model system for the human disease.