Insulin-like Growth Factor-2 (IGF2) Loss of Imprinting Marks a Field Defect Within Human Prostates Containing Cancer

Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
The Prostate (Impact Factor: 3.57). 04/2011; 71(15):1621-30. DOI: 10.1002/pros.21379
Source: PubMed


Loss of imprinting (LOI) is an epigenetic alteration involving loss of parental origin-specific expression at normally imprinted genes. A LOI for IGF2, a paracrine growth factor, has been implicated in the development of prostate and other cancers. In the current study, we define IGF2 LOI in histologically normal prostate tissues in relationship to tumor foci and gene expression.
Microdissected tumor associated (TA) adjacent (2 mm) and distant (10 mm) tissues surrounding tumor foci were generated. IGF2 imprinting in informative prostate tissue sets was quantitated using a fluorescent primer extension assay and expression analyzed utilizing quantitative PCR. DNA methylation analyses were performed using quantitative pyrosequencing.
A marked IGF2 LOI was found in adjacent TA tissues (39 ± 3.1%) and did not significantly decrease in tissues distant (38 ± 5.3%) from tumor foci (45 ± 2.9%; P = 0.21). IGF2 imprinting correlated with IGF2 expression in TA tissues, but not within the tumor foci. Hypomethylation of the IGF2 DMR0 region correlated with decreased IGF2 expression in tumors (P < 0.01). The expression of IGF2 and its adjacent imprinted gene H19 were increased in adjacent and distant tissues compared to tumors (P < 0.05) indicating the importance of factors other than LOI in driving IGF2 expression.
LOI of IGF2 occurs not only adjacent to prostate tumor foci, but is widely prevalent even in distant areas within the peripheral zone. These data provide evidence for a widespread epigenetic field defect in histologically normal tissues that might be employed to identify prostate cancer in patients.

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    • "It was also shown that heparanase (endo-β-D-glucuronidase) is overexpresed in PCa cells due to its substantial hypomethylation (Ogishima et al., 2005). More recently, it was demonstrated that several other genes, including histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), Melanoma Antigen Gene Protein-A11 (MAGE-11), nsulin-like Growth Factor-2 (IGF2), Cancer Testis Antigene (CTA) etc., are hypomethylated in PCa cells (Ribarska et al., 2012; Bhusari et al., 2011; Karpf et al., 2009; Yegnasubramanian et al. 2008). "
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    ABSTRACT: Prostate cancer belongs to the most common cancers and it is the second leading cause of cancer death in men. A genetic predisposition with epigenetic changes in DNA contributes to the development of the disease. DNA hypermethylation and hypomethylation belong to the most studied epigenetic changes in prostate cancer development. Both forms may lead to chromosomal instability and transcriptional gene silencing. This article is aimed at brief review of information in respect to DNA hypermethylation and hypomethylation in the prostate cancer development. Moreover, we discuss their implication for diagnosis and prognosis of prostate cancer.
    Full-text · Article · Jan 2015 · OnLine Journal of Biological Sciences
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    • "De novo DNA methylation is established during maternal folliculogenesis, and then modified again at fertilization38. Methylation of mono-allelically expressed imprinted genes is perturbed in prostate cancer cell models and aggressive prostate cancer foci39404142. For example, expression of the imprinted gene Insulin-like Growth Factor 2 (IGF2) is deregulated in prostate cancer lesions43. "
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    ABSTRACT: Developing recommendations for prostate cancer prevention requires identification of modifiable risk factors. Maternal exposure to high-fat diet (HFD) initiates a broad array of second-generation adult disorders in murine models and humans. Here, we investigate whether maternal HFD in mice affects incidence of prostate hyperplasia in offspring. Using three independent assays, we demonstrate that maternal HFD is sufficient to initiate prostate hyperproliferation in adult male offspring. HFD-exposed prostate tissues do not increase in size, but instead concomitantly up-regulate apoptosis. Maternal HFD-induced phenotypes are focally present in young adult subjects and greatly exacerbated in aged subjects. HFD-exposed prostate tissues additionally exhibit increased levels of activated Akt and deactivated Pten. Taken together, we conclude that maternal HFD diet is a candidate modifiable risk factor for prostate cancer initiation in later life.
    Full-text · Article · Dec 2013 · Scientific Reports
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    • "While studies have suggested a role for IGF2 and tissue factor pathway inhibitor-2 (TFPI2) LOI in prostate cancer [7-9], the literature is restricted largely to these two genes. Here, we present a comprehensive investigation of methylation patterns at imprinted genes in prostate cancer. "
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    ABSTRACT: Imprinting is an important epigenetic regulator of gene expression that is often disrupted in cancer. While loss of imprinting (LOI) has been reported for two genes in prostate cancer (IGF2 and TFPI2), disease-related changes in methylation across all imprinted gene regions has not been investigated. Using an Illumina Infinium Methylation Assay, we analyzed methylation of 396 CpG sites in the promoter regions of 56 genes in a pooled sample of 12 pairs of prostate tumor and adjacent normal tissue. Selected LOI identified from the array was validated using the Sequenom EpiTYPER assay for individual samples and further confirmed by expression data from publicly available datasets. Methylation significantly increased in 52 sites and significantly decreased in 17 sites across 28 unique genes (P < 0.05), and the strongest evidence for loss of imprinting was demonstrated in tumor suppressor genes DLK1, PLAGL1, SLC22A18, TP73, and WT1. Differential expression of these five genes in prostate tumor versus normal tissue using array data from a publicly available database were consistent with the observed LOI patterns, and WT1 hypermethylation was confirmed using quantitative DNA methylation analysis. Together, these findings suggest a more widespread dysregulation of genetic imprinting in prostate cancer than previously reported and warrant further investigation.
    Full-text · Article · Jul 2013 · BMC Urology
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