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

Wan-Heng Wang,Jian-Xiong Duan,Thanh H Vu,Andrew R Hoffman

doi:10.1074/jbc.271.44.27863

Wan-Heng Wang, Jian-Xiong Duan + Show 2 more

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https://doi.org/10.1074/jbc.271.44.27863

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Abstract

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.

Highlights

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
We demonstrate that LOI can be observed in some normal adjacent kidney tissue (NAT) samples and that IGF2 expression is increased in all categories of Wilms’ tumor tissues compared to NAT, suggesting that mechanisms other than LOI and loss of constitutional heterozygosity (LOH) with consequent biallelic expression of IGF2 can result in increased IGF2 mRNA abundance in Wilms’ tumors
To identify LOH in our 40 subjects with Wilms’ tumor, we determined the allelic genotypes of tyrosine hydroxylase (TH), insulin (INS), IGF2, and H19 at 11p15.5, and which LOH did not involve 11p13 (WT1) at 11p13 in the 40 Wilms’ tumor samples and in their paired normal adjacent kidney tissues (Fig. 1)

Summary

Introduction

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. A significant increase (>5fold) 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. A number of malignant tumors, including Wilms’ tumor, have been shown to contain abnormally high levels of IGF2 mRNA, and loss of IGF2 imprinting, where both paternal and maternal alleles are transcribed, has been observed in many of these tumors [7, 8]. We demonstrate that LOI can be observed in some NAT samples and that IGF2 expression is increased in all categories of Wilms’ tumor tissues compared to NAT, suggesting that mechanisms other than LOI and LOH with consequent biallelic expression of IGF2 can result in increased IGF2 mRNA abundance in Wilms’ tumors

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