Genomic Imprinting of the M6P/IGF2 Receptor: A Novel Breast Cancer Susceptibility Mechanism

摘要

Genomic imprinting is an epigenetic phenomenon in mammals that results in the differential expression of the paternally and maternally inherited alleles of a gene. 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 M6P/IGF2R has been shown to suppress cancer cell growth and is mutated in a number of human cancers, including those that develop in the lung, liver colon and breast. These findings are consistent with the M6P/IGF2R functioning normally as a tumor suppressor. We have shown that M6P/IGF2R imprinting and receptor IGF2 binding evolved in an ancestor common to marsupials and eutherian mammals. Although M6P/IGF2R is imprinted in lower eutherian mammals, it is not imprinted in humans, as has been proposed in the literature. Our results with breast cancer and Wilms tumor suggest that a mutational event within intron 10 of the M6P/IGF2R, and not disregulation of imprinting, may have resulted in the aberrant monoallelic expression observed in some humans. Therefore, although our evidence strongly indicates that M6P/IGF2R functions as a tumor suppressor in lung, liver, colon and breast cancer, genomic imprinting at this locus is likely not involved in the etiology of tumorigenesis.