Genomic imprinting and Wilms' tumor.
The selective loss of maternal and reduplication of paternal chromosome 11p15.5 alleles in Wilms' tumors (WTs) points to the existence of a paternally imprinted tumor suppressor gene(s) and/or a maternally imprinted dose-dependent growth-promoting gene(s) in this chromosomal region. Two reciprocally imprinted chromosome 11p15.5 genes, H19, a candidate tumor suppressor gene, and IGF2, a candidate dominant oncogene, have been well-characterized in terms of their imprinting and expression status in WTs. Here we review and extend data indicating that a majority of WTs show a bipaternal epigenotype at these loci, with H19 inactive and IGF2 biallelically active. This can arise either through loss of heterozygosity (LOH) or by a non-LOH pathway involving localized biallelic hypermethylation of H19 DNA. Conversion to this bipaternal endpoint 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 LOH and biallelic H19 hypermethylation can occur both early and late in tumor progression and since early loss is not associated with bilaterality or multifocality of WTs, these types of lesions appear to be permissive rather than rate-limiting in Wilms' tumorigenesis.
Moulton
T
T
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Chung
W Y
WY
Yuan
L
L
Hensle
T
T
Waber
P
P
Nisen
P
P
Tycko
B
B
D000483:Alleles; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019175:DNA Methylation; D004843:Epistasis, Genetic; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D005838:Genotype; D006128:Growth / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D020409:Molecular Motor Proteins; D005810:Multigene Family; D009124:Muscle Proteins / Q000235:genetics; D009857:Oncogenes / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D029701:Saccharomyces cerevisiae Proteins; D009396:Wilms Tumor / Q000235:genetics*
D005656:Fungal Proteins; C094335:H19 long non-coding RNA; C075341:KIP2 protein, S cerevisiae; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; D009124:Muscle Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D029701:Saccharomyces cerevisiae Proteins; D007335:Insulin-Like Growth Factor II