This review summarises the critical discussion at an international workshop held under the auspices of The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium, where the potential for drug development to target IGF2 and the WT epigenome was debated.
With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor.
This contrasts the situation we found at the IGF2/H19 locus, which shows high overexpression of IGF2 and inversely correlated expression of the H19 gene in WT.
This is the first comprehensive study of the four genes, and the results supported the hypothesis that the lower incidence of IGF2 LOI contributes to the lower incidence of WTs in Japanese children.
Overexpression of insulin-like growth factor 2 (IGF2), an imprinted gene located on chromosome 11p15, has been reported as a characteristic feature in various embryonal tumors, including Wilms tumor (WT).
We describe a family with overgrowth in three generations and Wilms' tumor in two generations, with paternal inheritance of a cis-duplication at 11p15.5 spanning the BWS IC1 region and including H19, IGFII, INS, and TH.
Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele.
Using molecular analysis, a loss of Wilms' tumor gene 1 (WT1) transcript and a biallelic expression of insulin growth factor 2 (IGF2) could be revealed.
We investigated whether the difference in incidence of Wilms' tumour between children of east-Asian descent and white children is due to variations in proportion of tumours with loss of IGF2 imprinting (IGF2 LOI).
IGF2-AS was expressed at levels comparable with IGF2 sense expression derived from promoters P1 and P2 in normal tissue and in breast, ovarian, and Wilms' tumor tissues.
However, some WTs with normal imprinting of IGF2 also show aberrant methylation of CTCF binding sites, indicating that methylation of these sites is necessary but not sufficient for LOI in WT.
Genomic imprinting of insulin-like growth factor 2 (IGF2) has been shown to play an important role in the development of Wilms' tumor and adult cancers including lung and esophageal cancer.
Interestingly, PEG8/IGF2AS and IGF2 were found to be overexpressed in Wilms' tumor samples, at levels over ten and a hundred times higher than that in normal kidney tissues neighboring the tumors, respectively.
In addition, the analysis of the expression of other 11p15 imprinted genes and kidney-developmentally regulated genes indicates that IGF2 overexpression, inappropriate coexpression of RET and GDNF and, in some cases, down-regulation of CDKN1C may also play an important role in the pathogenesis of WT.