GENOMIC IMPRINTING AND WILMS-TUMOR

The selective loss of maternal and reduplication of paternal chromosom e 11p15.5 alleles in Wilms' tumors (WTs) points to the existence of a paternally imprinted tumor suppressor gene(s) and/or a maternally impr inted dose-dependent growth-promoting gene(s) in this chromosomal regi on. Two reciprocally imprinted chromosome 11p15.5 genes, H19, a candid ate tumor suppressor gene, and IGF2, a candidate dominant oncogene, ha ve been well-characterized in terms of their imprinting and expression status in WTs. Here we review and extend data indicating that a major ity of WTs show a bipaternal epigenotype at these loci, with H19 inact ive and IGF2 biallelically active. This can arise either through loss of heterozygosity (LOH) or by a non-LOH pathway involving localized bi allelic hypermethylation of H19 DNA. Conversion to this bipaternal end point has recently been found to affect not only these two genes, but also at least one other imprinted 11p15.5 gene, KIP2. Since 11p15.5 LO H and biallelic H19 hypermethylation can occur both early and late in tumor progression and since early loss is not associated with bilatera lity or multifocality of WTs, these types of lesions appear to be perm issive rather than rate-limiting in Wilms' tumorigenesis. (C) 1996 Wil ey-Liss, Inc.