Imprinting of a Genomic Domain of 11p15 and Loss of Imprinting in Cancer

Andrew Feinberg
Department of Medical Oncology and Molecular Biology and Genetics; Johns Hopkins University School of Medicine

Our laboratory has found genomic imprinting of a large genomic domain of human 11p15.5, identifying several imprinted genes within this domain: (1) insulin-like growth factor-II (IGF2), an important autocrine growth factor in a wide variety of malignancies; (2) H19, an untranslated RNA whose imprinting is linked to IGF2; (3) p57KIP2, a cyclin-dependent kinase inhibitor that causes G1/S arrest; (4) KvLQT1, a voltage-gated potassium channel; (4) TSSC3, a gene homologous to mouse TDAG51, which is implicated in Fas-mediated apoptosis; and (5) TSSC5, a putative transmembrane protein-encoding gene. We hypothesize the 11p15 harbors a large domain of imprinted growth-regulatory genes important in cancer. Five lines of evidence support this hypothesis: (1) We have discovered a novel genetic alteration in cancer, loss of imprinting (LOI), affecting several of these genes, and this is one of the most common genetic changes in human cancer. (2) We have found that the hereditary disorder Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and causes prenatal overgrowth, involves alterations in p57KIP2, IGF2, H19, and KvLQT1. (3) Imprinting within this domain appears to be developmentally regulated. (4) We have found both genetic (mutations) and epigenetic alterations (DNA methylation) in cancer; and (5) 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.