Imprinting Evolution and Cancer

Randy Jirtle
Department of Radiation Oncology; Duke University Medical Center

Imprinted genes normally function to control embryonic growth and development. They also are involved in cancer because their functional haploid state makes them vulnerable to being either inactivated or overexpressed. The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) targets lysosomal enzymes to the lysosomes, and regulates the bioavailability of extracellular growth factors such as TGFß1 and IGF2. We have shown that M6P/IGF2R is mutated early and frequently in a number of cancers, including those in liver, breast and lung. It is imprinted in mice, but postnatal M6P/IGF2R imprinting in humans is a polymorphic trait, with most individuals expressing both alleles. This marked species difference in M6P/IGF2R imprinting between mice and humans provides a plausible explanation for the enhanced sensitivity of mice to tumor formation, and also has implications concerning carcinogen risk assessment based on animal models. These unique M6P/IGF2R characteristics make this gene a valuable model for investigating imprint-induced cancer susceptibility, somatic propagation of imprinting and the phylogenetic origin of imprinting. (This research was supported in part by NIH grants CA25951and ES08823, DOD grant DAMDl7-98-1-8305, AstraZeneca, Ltd., Rohm and Haas, Inc. and Sumitomo Chemical Co., Ltd.).