Imprinted genes at 11p15.5 fall into two clusters, H19/IGF2 and KCNQ1 (Figure 2), regulated through separate imprinting control regions (ICR) that each controls expression of a number of genes within the cluster16. The H19/IGF2 ICR is regulated through a differentially methylated region (DMR) that is normally methylated only on the paternal chromosome. Binding of the insulator protein CTCF in the ICR is permitted only on the unmethylated maternal chromosome, resulting in expression of IGF2 only from the paternal methylated chromosome and expression of H19 from the choromosome17. The breast cancer paternally associated marker rs3817198 resides within LSP1, 100 kb downstream of H19 and within the same LD block. The effect of this marker on breast cancer could thus be through the H19/IGF2 imprinted locus. Loss of imprinting (LOI) at the H19/IGF2 locus, resulting in activation of IGF2 expression, has been reported in a number of different tumor types18. Furthermore, LOI at the H19/IGF2 locus in normal tissue has also been shown to predispose to colorectal cancer18.
