IMPRINTED GENES IN LIVER CARCINOGENESIS

Each cell contains both maternal and paternal copies of all genes exce pt those that reside on the sex chromosomes, However, because of a phe nomenon termed genomic imprinting, genes are biallelically expressed, Imprinted genes play an important role in embryogenesis and recently h ave also been shown to be mechanistically involved in carcinogenesis, The growing list of imprinted genes implicated in tumor formation incl udes both a growth factor gene, insulin-like growth factor 2 (IGF2), a nd a receptor gene, mannose 6-phosphate/insulin-like growth factor 2 r eceptor (M6P/IGF2R). Elevated expression of IGF2 is often found in tur ners, and loss of imprinting is one mechanism by which its expression is deregulated, The M6P/IGF2R functions in the inactivation of the mit ogen IGF2 and in the activation of the growth inhibitor, transforming growth factor beta, Recently, a high frequency of loss of heterozygosi ty with concomitant mutations in the remaining allele has been shown t o occur at the M6P/IGF2R locus (i.e., 6q26-q27) in both human liver an d breast tumors, suggesting that this gene functions as a tumor suppre ssor, Expression of the M6P/IGF2R gene is biallelic hi most humans but is monoallelic in mice, This species difference hi M6P/IGF2R gene imp rinting provides one plausible explanation for the enhanced sensitivit y of mice to tumor formation, Furthermore, these findings suggest that species differences in the imprinted status of genes mechanistically involved in tumor formation should be factored into human carcinogenes is risk assessment models when extrapolating results from mice to huma ns.