CODING MUTATIONS IN P57(KIP2) ARE PRESENT IN SOME CASES OF BECKWITH-WIEDEMANN-SYNDROME BUT ARE RARE OR ABSENT IN WILMS-TUMORS

The Beckwith-Wiedemann syndrome (BWS) is marked by fetal organ overgro wth and conveys a predisposition to certain childhood tumors, includin g Wilms tumor (WT). The genetics of BWS have implicated a gene that ma ps to chromosome 11p15 and is paternally imprinted, and the gene encod ing the cyclin-cdk inhibitor p57(KIP2) has been a strong candidate. By complete sequencing of the coding exons and intron/exon junctions, we found a maternally transmitted coding mutation in the cdk-inhibitor d omain of the KIP2 gene in one of five cases of BWS. The BWS mutation w as an in-frame three-amino-acid deletion that significantly reduced bu t did not fully abrogate growth-suppressive activity in a transfection assay. In contrast, no somatic coding mutations in KIP2 were found in a set of 12 primary WTs enriched for cases that expressed KIP2 mRNA, including cases with and without 11p15.5 loss of heterozygosity. Two o ther 11p15.5 loci, the linked and oppositely imprinted H19 and IGF2 ge nes, have been previously implicated in WT pathogenesis, and several o f the tumors with persistent KIP2 mRNA expression and absence of KIP2 coding mutations showed full inactivation of H19. These data suggest t hat KIP2 is a BWS gene but that it is not uniquely equivalent to the 1 1p15.5 ''WT2'' tumor-suppressor locus.