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Kaneda, A. & Feinberg, A. P. Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res. 65, 11236-11240

Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States
Cancer Research (Impact Factor: 9.28). 01/2006; 65(24):11236-40. DOI: 10.1158/0008-5472.CAN-05-2959
Source: PubMed

ABSTRACT Epigenetic alterations in cancer occur at least as commonly as genetic mutations, but epigenetic alterations could occur secondarily to the tumor process itself. To establish a causal role of epigenetic changes, investigators have turned to genetically engineered mouse models. Here, we review a recent study showing that a mouse model of loss of imprinting (LOI) of the insulin-like growth factor II gene (Igf2), which shows aberrant activation of the normally silent maternal allele, modifies the risk of intestinal neoplasia caused by mutations of the adenomatous polyposis coli (Apc) gene. This increased risk corresponds to the apparent increased risk of colorectal cancer in patients with LOI of IGF2. The model suggests that preexisting epigenetic alterations in normal cells increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells, providing a novel idea for cancer risk management.

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    • "In disease states, imprinted expression can also be lost. For example, many cases of human colorectal cancer are associated with loss of imprinted expression that results in biallelic IGF2 expression (Kaneda and Feinberg, 2005). The examples described above involve tissue-specific gain or loss of imprinted expression for genes that show widespread or 'ubiquitous' imprinted expression in embryonic or adult tissues and in extraembryonic tissues, which comprise the short-lived placenta and membranes that support the developing embryo in utero. "
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    ABSTRACT: Imprinted genes in mice and humans mainly occur in clusters that are associated with differential DNA methylation of an imprint control element (ICE) and at least one nonprotein-coding RNA (ncRNA). Imprinted gene silencing is achieved by parental-specific insulator activity of the unmethylated ICE mediated by CTCF (CCCTC-binding factor) binding, or by ncRNA expression from a promoter in the unmethylated ICE. In many imprinted clusters, some genes, particularly those located furthest away from the ICE, show imprinted expression only in extraembryonic tissues. Recent research indicates that genes showing imprinted expression only in extraembryonic tissues may be regulated by different epigenetic mechanisms compared with genes showing imprinted expression in extraembryonic tissues and in embryonic/adult tissues. The study of extraembryonic imprinted expression, thus, has the potential to illuminate novel epigenetic strategies, but is complicated by the need to collect tissue from early stages of mouse development, when extraembryonic tissues may be contaminated by maternal cells or be present in limited amounts. Research in this area would be advanced by the development of an in vitro model system in which genetic experiments could be conducted in less time and at a lower cost than with mouse models. Here, we summarize what is known about the mechanisms regulating imprinted expression in mouse extraembryonic tissues and explore the possibilities for developing an in vitro model.
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    • "Perhaps the most well studied example in adult cancers is the IGF2 gene, whose biallelic expression would result in overproduction of a potent growth factor (Feinberg and Tycko 2004; Feinberg 2005; Holm et al. 2005; Feinberg et al. 2006). LOI for IGF2 is found in normal-appearing colonic epithelium of patients with colorectal cancer and may be associated with increased risk of colon cancer even when found in circulating white cells (Cui et al. 2003; Kaneda and Feinberg 2005; Sakatani et al. 2005). The LOI mechanism is a complicated one. "
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    ABSTRACT: It is increasingly apparent that cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes, which convey heritable gene expression patterns critical for neoplastic initiation and progression. These aberrant epigenetic mechanisms are manifest in both global changes in chromatin packaging and in localized gene promoter changes that influence the transcription of genes important to the cancer process. An exciting emerging theme is that an understanding of stem cell chromatin control of gene expression, including relationships between histone modifications and DNA methylation, may hold a key to understanding the origins of cancer epigenetic changes. This possibility, coupled with the reversible nature of epigenetics, has enormous significance for the prevention and control of cancer.
    Genes & Development 01/2007; 20(23):3215-31. DOI:10.1101/gad.1464906 · 12.64 Impact Factor
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    • "In that one informative heterozygous case, RT-PCR revealed IGF2 transcripts generated from each of the two alleles identified by PCR on genomic DNA. This biallelic expression indicates a loss of IGF2 imprinting, similar to that which has been noted in other cancers associated with IGF2 overexpression (Zumkeller and Westphal, 2001; Kaneda and Feinberg, 2005; Sakatani et al., 2005). "
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    ABSTRACT: Central neurocytoma (CN) is a rare periventricular tumor, whose derivation, lineage potential, and molecular regulation have been mostly unexplored. We noted that CN cells exhibited an antigenic profile typical of neuronal progenitor cells in vivo, yet in vitro generated neurospheres, divided in response to bFGF (basic fibroblast growth factor), activated the neuroepithelial enhancer of the nestin gene, and gave rise to both neuron-like cells and astrocytes. When CN gene expression was compared with that of both normal adult VZ (ventricular zone) and E/nestin:GFP (green fluorescent protein)-sorted native neuronal progenitors, significant overlap was noted. Marker analysis suggested that the gene expression pattern of CN was that of a proneuronal population; glial markers were conspicuously absent, suggesting that the emergence of astroglia from CN occurred only with passage. The expression pattern of CN was distinguished from that of native progenitor cells by a cohort of differentially expressed genes potentially involved in both the oncogenesis and phenotypic restriction of neurocytoma. These included both IGF2 and several components of its signaling pathway, whose sharp overexpression implicated dysregulated autocrine IGF2 signaling in CN oncogenesis. Both receptors and effectors of canonical wnt signaling, as well as GDF8 (growth differentiation factor 8), PDGF-D, and neuregulin, were differentially overexpressed by CN, suggesting that CN is characterized by the concurrent overactivation of these pathways, which may serve to drive neurocytoma expansion while restricting tumor progenitor phenotype. This strategy of comparing the gene expression of tumor cells to that of the purified native progenitors from which they derive may provide a focused approach to identifying transcripts important to stem and progenitor cell oncogenesis.
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