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Susan K. Murphy, Ph.D.
Duke University Medical Center
Epigenetic Alterations in Ovarian Cancer
Project Summary
The molecular mechanisms involved in the development of ovarian cancer are poorly understood, and epigenetic mutations that contribute to the disease have been infrequently identified. ‘Epigenetic’ changes represent an alternative mechanism to disrupt gene expression that occurs through modification of DNA by the attachment of methyl groups (consisting of one carbon and three hydrogen atoms). In cancer cells, inappropriate epigenetic changes can result in uncontrolled cell growth by shutting down growth inhibitors and/or turning on growth stimulators. Imprinted genes are particularly sensitive to epigenetic changes. These genes are typically involved in regulating growth and the maternal and paternal copies normally exhibit opposite patterns of DNA methylation. This epigenetic parental distinction enables imprinted genes to always be expressed from only one of the two inherited chromosomes. The imprinted PEG3 (Paternally Expressed Gene 3) and the IGF2 (insulin-like Growth Factor 2) exhibit abnormal expression in ovarian cancer. An important objective of this research is to determine whether this can be attributed to changes in the methylation patterns associated with these genes. IGF2 encodes a powerful growth-enhancing protein that is kept in check by the foundation of the tumor suppressor gene, M6P/IGF2R (Mannose 6-Phosphate/Insulin-like Growth Factor Receptor). The genomic region encoding the M6P/IGF2R is frequently deleted in many types of cancer. Further, this work will determine whether changes in IGF2 methylation and expression occur together with deletions of the M6P/IGF2R to provide tumors with enhanced growth potential. Studies have shown that in addition to colon cancer cells, abnormal methylation of IGF2 is present in the surrounding normal colonic tissue and in the white blood cells of many colon cancer patients. These findings suggest that some people are susceptible to cancer because they do not maintain proper methylation of imprinted genes in their normal tissues. Therefore, methylation defects in the imprinted genes proposed fr study in ovarian cancer will also be assessed for their methylation status in white blood cells to determine if such a test will allow for identification of individuals at high risk of developing ovarian and other cancers.
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