Increased expression of the insulin-like growth factor-II gene in Wilms' tumor is not dependent on loss of genomic imprinting or loss of heterozygosity.
Loss of imprinting of insulin-like growth factor-II gene (IGF2) and/or loss of heterozygosity at the 11p15 loci have been postulated to be responsible for IGF2 overexpression in Wilms' tumor. In order to delineate the mechanism of IGF2 overexpression in Wilms' tumors, we have genotyped the 11p15-11p13 chromosomal region and determined allelic expression of IGF2 and H19 in both tumor tissue and in normal adjacent kidney tissue from 40 patients with Wilms' tumor. In five of the eight subjects informative for the ApaI IGF2 polymorphism, loss of imprinting of IGF2 was observed in both normal and tumor tissues. A significant increase (>5-fold) in IGF2 expression in tumor tissues compared to the normal adjacent kidney tissue was observed regardless of the IGF2 imprinting or the chromosome 11p15 heterozygosity status. In each case, the overexpression of IGF2 in the tumors was accompanied by activation of all four IGF2 promoters. Our data indicate that alterations of IGF2 imprinting occurred in normal adjacent kidney tissue before tumorigenesis and that the IGF2 overexpression in Wilms' tumor tissue occurs through a loss of heterozygosity- or loss of imprinting-independent process.
Medical Service and GRECC, Veterans Affairs Palo Alto Health Care System and Department of Medicine, Stanford University School of Medicine, Palo Alto, California 94304, USA. hoffman@camis.stanford.edu
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D000483:Alleles; D001483:Base Sequence; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics; D015252:Deoxyribonucleases, Type II Site-Specific; D015870:Gene Expression; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D014157:Transcription Factors / Q000235:genetics; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; D007335:Insulin-Like Growth Factor II; D015252:Deoxyribonucleases, Type II Site-Specific; C038485:GGGCCC-specific type II deoxyribonucleases