Relaxation of IGF2 and KIP2 imprinting in Wilms tumours and other urogenital tumours

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Relaxation of IGF2 imprinting occurs in Wilms tumours and many other solid tumours, but the mechanism of loss of imprinting (LOI) has not yet been determined. To investigate the role of altered DNA methylation in relaxation of genomic imprinting, we have examined the pattern of DNA methylation within the complete human IGF2 gene and KIP2 gene in Wilms tumours and other urogenital tumours that have either lost or retained IGF2 imprinting. Relaxation of imprinting involves loss of the maternal imprint from the three imprinted IGF2 promoters (P2, P3 and P4) which are clustered together within a CpG island. Methylation analysis of the IGF2 CpG island showed that these three imprinted promoters were unmethylated in all Wilms tumours and in the normal kidney. However, this analysis identified a region of allele specific DNA methylation on the maternal IGF2 allele between exons 2 and 3, upstream of the imprinted IGF2 promoters, that is present in tumours with normal imprinted IGF2 expression, but lost in tumours with relaxation of imprinting. In addition a boundary of DNA methylation was found at two ALU repeat elements in intron 1 that may be involved in the imprinting process. In contrast, KIP2 gene was entirely unmethylated in all tumours and normal kidneys. From these results we postulate the existence of an upstream cis-acting methylation center in the human IGF2 that may co-ordinately control expression and imprinting from the down stream promoters. However, KIP2 gene seems to be under independent regulation of IGF2/H19 imprinting domain.