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  1. Genomic imprinting is an epigenetic modification of a specific parental allele of a gene, or the chromosome on which it resides, in the gamete or zygote leading to differential expression of the two alleles of the gene in somatic cells of the offspring.

  2. Evidence for genomic imprinting in normal development derives from studies over many years of the whole genome, specific chromosomal regions, and individual imprinted loci. There is now an intense search for an ever-increasing list of imprinted genes that are involved in many different types of cellular processes.

  3. Genomic imprinting challenges two assumptions of Mendelian genetics applied to human disease: that the maternal and paternal alleles of a gene are equivalent and that two functional copies of a gene always are associated with health. Imprinted genes probably account for many examples of developmental malformations in humans.

  4. Hydatidiform moles and complete ovarian teratomas, the genome of each of which is derived from a single parental origin, show that an imbalance of maternal and paternal genome equivalents leads to neoplastic growth.

  5. Several chromosomes show parental origin-specific alterations in cancer, including losses of heterozygosity in Wilms tumor and in acute myelocytic leukemia and gene amplification in neuroblastoma.

  6. Beckwith-Wiedemann syndrome, a disorder of prenatal overgrowth and cancer, sometimes involves parental origin-specific germ-line chromosomal rearrangements and uniparental disomy.

  7. Loss of imprinting (LOI) is a recently discovered alteration in cancer that involves loss of parental origin-specific gene expression. LOI may include activation of the normally silent copy of growth-promoting genes and/or silencing of the normally transcribed copy of tumor suppressor genes. These changes can involve a switch of a maternal chromosome to a paternal epigenotype.

  8. There is a rapidly increasing number of examples of genes and tumors that show LOI. Genes include IGF2, H19, and p57KIP2 . Tumors include Wilms tumor; hepatoblastoma; rhabdomyosarcoma; Ewing sarcoma; uterine, cervical, esophageal, prostate, lung, and colon cancer; choriocarcinoma; and germ-cell tumors. Thus LOI is one of the most common alterations in human cancer.

  9. Normal genomic imprinting is maintained in part by parental origin-specific, tissue-independent DNA methylation of cytosine within CpG islands, regions rich in CpG dinucleotides. Tumors with LOI show abnormal methylation of these CpG islands.

  10. Normal genomic imprinting should be viewed as a developmental process rather than as a single event. Thus a combination of both cis-acting and trans-acting signals is likely to be important in the establishment and maintenance of normal genomic imprinting, and disruption of these same factors can be expected to play a role in LOI in cancer.

  11. Since normal imprinting is reversible, LOI also may be reversible and amenable to novel therapeutic approaches, such as modification with 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation.

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