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WT2 is defined by maternal-specific loss of heterozygosity (LOH) on chromosome 11p15.5 in Wilms' tumors (WTs). The imprinted  H19  gene, in this region, is silenced and hypermethylated in most WTs, and this is linked to pathological biallelic expression of  IGF2 . However,  H19  and  IGF2  lie within a larger imprinted domain, and the gene specificity of  H19  epimutation has been a persistent question. To address this, we assessed LOH, gene expression and DNA methylation at multiple sites in and around the imprinted domain. LOH mapping showed that the entire domain, including  IGF2/H19 , is within the minimal WT2 region. Genes within the domain, including  IPL/TSSC3/ BWR1C, IMPT1/ORCTL2/BWR1AA/TSSC5, KvLQT1/ KCNA9  and  TAPA1/CD81 , as well as the zinc finger gene  ZNF195/ZNFP104  near the centromeric border, were expressed persistently in many WTs. DNA hypermethylation was not detected with 5′ upstream probes for  IPL ,  IMPT1 ,  KvLQT1  and  ZNF195  in WTs or WT-associated kidneys. Fully developed WTs showed variable hypomethylation at an imprinted CpG island in a  KvLQT1  intron, but this was only complete in the cases with LOH and was not observed in pre-neoplastic WT-associated kidneys with  H19  epimutation. Analysis of the corresponding region of mouse chromosome 7 using methyltransferase-hypomorphic mice showed that the  H19  imprint was fully erased, but that the allelic bias at  IpI ,  Impt1 ,  p57Kip2  and, to a lesser extent,  Kvlqt1 , persisted. Pre-existing massive allelic asymmetry for DNA methylation and hyper-dependence of transcription on methylation status may underlie the mechanism of gene-specific silencing of  H19  in Wilms' tumorigenesis.

human molecular genetics

Multipoint Analysis of Human Chromosome 11p15/ Mouse Distal Chromosome 7: Inclusion of  H19/IGF2  in the Minimal WT2 Region, Gene Specificity of  H19  Silencing in Wilms' Tumorigenesis and Methylation Hyper-Dependence of  H19  Imprinting