Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer.
ABSTRACT 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.
SourceAvailable from: Timothy Barrow
Article: Epigenetic Epidemiology of Cancer.[Show abstract] [Hide abstract]
ABSTRACT: Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.Biochemical and Biophysical Research Communications 08/2014; 455(1-2). DOI:10.1016/j.bbrc.2014.08.002 · 2.28 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Diet is hypothesized to be a critical environmentally related risk factor for prostate cancer (PCa) development, and specific diets and dietary components can also affect PCa progression; however, the mechanisms underlying these associations remain elusive. As for a maturing organism, PCa’s epigenome is plastic and evolves from the pre-neoplastic to the metastatic stage. In particular, epigenetic remodeling relies on substrates or cofactors obtained from the diet. Here we review the evidence that bridges dietary modulation to alterations in the prostate epigenome. We propose that such diet-related effects offer a mechanistic link between the impact of different diets and the course of PCa development and progression.Oncogene 12/2014; DOI:10.1038/onc.2014.422 · 8.56 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Cancer is caused by a combination of genetic alterations and gross changes to the epigenetic landscape that together result in aberrant cancer gene regulation. Therefore, we need to fully sequence both the cancer genome and the matching cancer epigenomes before we can fully integrate the suite of molecular mechanisms involved in initiation and progression of cancer. A further understanding of epigenetic aberrations has a great potential in the next era of molecular genomic pathology in cancer detection and treatment in all types of cancer, including prostate cancer. In this review, we discuss the most common epigenetic aberrations identified in prostate cancer with the biomarker potential. We also describe the innovative and current epigenomic technologies used for the identification of epigenetic-associated changes in prostate cancer and future translational applications in molecular pathology for cancer detection and prognosis.Oncogene advance online publication, 19 May 2014; doi:10.1038/onc.2014.111.Oncogene 05/2014; DOI:10.1038/onc.2014.111 · 8.56 Impact Factor