Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

• Published in: Oncogene Vol. 18; no. 52; pp. 7527 - 7534
• Main Authors: SULLIVAN, M. J, TANIGUCHI, T, JHEE, A, KERR, N, REEVE, A. E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 09.12.1999; Nature Publishing Group
• Subjects: Alleles; Animals; Biological and medical sciences; Blotting, Southern; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Deoxyribonuclease HpaII - genetics; Deoxyribonuclease HpaII - metabolism; DNA Methylation; Exons; Fundamental and applied biological sciences. Psychology; Genomic Imprinting; Humans; IGF2 gene; Insulin; Insulin-like growth factor II; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Kidney - physiology; Kidney Neoplasms - genetics; Kidneys; Mice; Molecular and cellular biology; Molecular Sequence Data; Promoters; Regulatory Sequences, Nucleic Acid; Tumors; Wilms Tumor - genetics; Wilms' tumor; Kidney disease; Human; Urinary system disease; Gene; Wilms tumor; Loss of imprinting; Malignant tumor; Gene expression; Methylation; Carcinogenesis; Insulin like growth factor 2; Genomic imprinting
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203096

Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three 'differentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allele-specific DNA methylation was identified spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-specific differential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other differential methylation was identified. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-specific methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately influence imprinting.