Loss of imprinting of IGF2 correlates with hypomethylation of the H19 differentially methylated region in the tumor tissue of colorectal cancer patients

Abstract

Expression of the imprinted genes insulin-like growth factor 2 (IGF2) and H19 depends on the methylation pattern of their differentially methylated region (DMR) located on chromosome 11p15. In the present study, we examined the imprinting status of the IGF2 gene in 120 human colorectal cancer (CRC) patients and 150 normal controls. In addition, we analyzed the DNA methylation of the sixth CTCF-binding site in the DMR of IGF2/H19 in 81 CRC patients using bisulfate sequencing. Of a total of 81 informative (heterozygous) samples, 51 samples showed bialleic IGF2 expression in tumor samples; however, only 15 of 69 informative samples showed loss of imprinting (LOI) of IGF2 in normal controls. Statistically significant differences in the methylation status between the retention of imprinting (ROI) and LOI groups (66.1±14.9 vs. 16.7±9.2, p=0.008) were observed. The results of the present study suggest that LOI of IGF2 is important in the carcinogenesis of CRC. Hypomethylation of the sixth CTCF-binding site in the DMR of IGF2/H19 is linked to LOI and the common IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to human CRC.