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Imprinting of a Genomic Domain of 11p15 and Loss of Imprinting in Cancer: An Introduction¹

Departments of Medicine, Oncology, and Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

² To whom requests for reprints should be addressed, at Johns Hopkins University School of Medicine, 1064 Ross, 720 Rutland Avenue, Baltimore, MD 21205.

Our laboratory has found genomic imprinting of a large genomic domain of human 11p15.5, identifying six imprinted genes within this domain: (a) insulin-like growth factor II (IGF-II), an important autocrine growth factor in a wide variety of malignancies; (b) H19, an untranslated RNA that is a putative growth suppressor gene regulating IGF-II; (c) p57^KIP2, a cyclin-dependent kinase inhibitor that causes G₁-S arrest; (d) K_VLQT1, a voltage-gated potassium channel; (e) TSSC3, a gene that is homologous to mouse TDAG51, which is implicated in Fas-mediated apoptosis; and (f) TSSC5, a putative transmembrane protein-encoding gene. We hypothesize that 11p15 harbors a large domain of imprinted growth-regulatory genes that are important in cancer. Several lines of evidence support this hypothesis: (a) we have discovered a novel genetic alteration in cancer, loss of imprinting, which affects several of these genes, and is one of the most common genetic changes in human cancer; (b) we have found that the hereditary disorder Beckwith-Wiedemann syndrome, which predisposes to cancer and causes prenatal overgrowth, involves alterations in p57^KIP2, IGF-II, H19, and K_VLQT1; (c) we have found both genetic (somatic mutation in Wilms' tumor) and epigenetic alterations (DNA methylation) in cancer; and (d) we can partially reverse abnormal imprinting using an inhibitor of DNA methylation. We propose a model of genomic imprinting as a dynamic developmental process involving a chromosomal domain. According to this model, cancer involves both genetic and epigenetic mechanisms affecting this imprinted domain and the genes within it.

¹ Presented at the "General Motors Cancer Research Foundation Twentieth Annual Scientific Conference: Developmental Biology and Cancer," June 9–10, 1998, Bethesda, MD. This work was supported by NIH Grant CA65145.

Received 12/ 4/98. Accepted 2/ 1/99.

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