Significance of Faulty Imprinting in Cancer

Feinberg and colleagues attached special significance to LOI in cancer and they initiated a search for the mechanism by which this epigenetic change might enhance the risk to neoplasia. In the first of two papers, Cui et al. found that LOI of the insulin-like growth factor II (IGF2) gene, a feature common to many human cancers, occurred in about 10% of the normal human population.117 LOI in this segment of the population increased the risk of colorectal cancer about 3.5-to 5-fold, suggesting that faulty imprinting was related to the risk of cancer.

In the second paper, Sakatani et al. created a mouse model to investigate the mechanism by which LOI of Igf2 contributed to intestinal cancer.118 They knew from the work of others that imprinting of Igf2 was regulated by a differentially methylated region (DMR) upstream of the nearby untranslated H19 gene, and that deletion of the DMR would lead to biallelic expression (LOI) of Igf2 in the offspring. To model intestinal neoplasia, they used Min mice with an Apc mutation with or without a maternally inherited deletion, i.e., with or without LOI, and they designed the model to mimic closely the human situation where LOI caused only a modest increase in IGF2 expression. They created their model of Igf2 LOI by crossing female heterozygous carriers of deletion (H19+/~) with male heterozygous carriers of the Apc+/Min. Their results showed that LOI mice developed twice as many intestinal tumors as control littermates, and they also showed a shift toward a less differentiated normal intestinal epithelium. In a comparative study of human tissues, a similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. These observations suggested that impairment of normal parental imprinting might interfere with cellular differentiation and thereby increase the risk of cancer. In more general terms, the results suggested that mutation of a cancer gene (APC) and an epigenetically imposed delay in cell maturation may act synergistically to initiate tumor development.114

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