REDUCED EXPRESSION OF THE CYCLIN-DEPENDENT KINASE INHIBITOR GENE P57(KIP2) IN WILMS-TUMOR

We have previously shown that the p57(KIP2) gene, which encodes a cycl in-dependent kinase inhibitor, undergoes genomic imprinting and lies w ithin a 700-kb domain of imprinted genes on 11p15, including IGF2 and H19, Loss of heterozygosity and loss of imprinting (LOI) of this regio n are frequently observed in Wilms' tumor (WT) and other embryonal mal ignancies, Although LOI of p57(KIP2) was observed in some WTs (similar to 10%), allele-specific expression was preserved in most tumors exam ined, Because our initial studies were inconclusive concerning the abs olute expression level of p57(KIP2) in WT, we developed a sensitive an d quantitative RNase protection assay to determine if changes in p57(K IP2) expression play a role in WT. Expression of p57(KIP2) was found t o he virtually absent in 21 of 21 WTs compared to matched normal kidne y from the same patients, as well as compared to fetal kidney. We also examined p57(KIP2) expression in the normal kidney and tongue of pati ents with Beckwith-Wiedemann syndrome (BWS), which predisposes to WT a nd also involves LOI of IGF2 and H19, Although p57(KIP2) was undetecta ble in BWS tongue, similar results were also observed in postnatal non -BWS tongue samples. Most primary skin fibroblast cultures of BWS cell lines exhibited normal imprinting of p57(KIP2). However, one BWS pati ent did show LOI of p57(KIP2) in skin fibroblasts, Thus, p57(KIP2) is part of a domain of genes on 11p15 that show altered expression and, i n some cases, altered imprinting in WT and BWS.