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Serum Epigenetic Markers and the Early Detection of Breast Cancer
Background: Mammography has reduced breast cancer mortality through early tumor detection. False-positive results and excess lifetime exposure to radiation are a concern, leaving a need for alternative markers for breast cancer detection. Epigenetic silencing of tumor suppressor genes through promoter hypermethylation is one of the most frequent alterations seen in human cancer. It is possible to detect changes in gene promoter methylation status, in both breast tumor tissue and the serum of breast cancer patients. These changes are thought to occur early in tumor development making them potential markers for early tumor detection. Objective/Hypothesis: To determine the potential of promoter methylation patterns, detected in serum, as markers for early breast cancer detection. A panel of 6 cancer-related genes (RASSF1A, CDKN2A, GSTP1, RARbeta2, ERbeta and DAPK) has been selected. Studies have found the promoters of these genes to be hypermethylated in breast cancer cases. These changes have been detected in both breast tumor tissue and serum/plasma. It is hypothesized that the methylation status of this panel of genes will act as an early marker for breast tumor detection in women prior to clinical presentation of disease. Specific Aims: To examine the ability of the promoter methylation status of each gene and/or their combination, in pre-diagnostic serum samples, to identify women with breast cancer, and distinguish them from cancer-free controls. The association between promoter methylation status and known tumor prognostic indicators will also be examined in cases. Study Design: This will be a case-control study nested within the XXXX cohort. In total, 14, 275 healthy women between the ages of 35 and 65 were enrolled in the study and donated blood between 1985 and 1991. A total of 1,006 invasive breast cancer cases have since been diagnosed and for 113 of these cases, serum samples were collected within 6 months prior to clinical diagnosis. For each case two healthy cancer-free controls will be selected, matching the case on age and time of blood donation (plus or minus 6 months). DNA will be isolated using commercially available kits and treated with sodium bisulfite. Promoter methylation status of sodium bisulfite treated DNA will then be analyzed using fluorescence based real-time PCR. Statistical tools appropriate for the assessment of diagnostic tests will be used. Potential Outcomes and Benefits: Early breast cancer diagnosis is a significant determinant of breast cancer survival. There is a need for sensitive and specific serum tumor markers to be used as part of a screening program, alone or in conjunction with mammography. This study seeks to determine whether promoter methylation status of tumor suppressor genes, detected in serum, may be used as such a marker and therefore as a tool for early tumor detection.
Breast cancer is the most common cancer among women in North America. Mammography screening has reduced mortality from breast cancer through early detection of disease. However, radiation exposure and the occurrence of false-positive results with the associated anxiety are a concern. There remains a need for a sensitive and specific marker of breast cancer to be used alone or in conjunction with mammography. Recent studies have shown that breast cancer patients have a number of genes turned off by promoter hypermethylation. Some of these genes are those that are responsible for maintaining normal cell growth, so when they are turned off, the cells grow unchecked and this can lead to tumor development. Gene promoter hypermethylation is thought to occur early on in cancer development, suggesting that its detection may be useful for early breast cancer diagnosis. It is possible to measure gene promoter hypermethylation in the blood of cancer patients as well as in the tumor tissue. The objective of this study is to determine if gene promoter methylation changes can be observed in women 6 months before they are diagnosed with breast cancer. If so, these assays could supplement mammography to improve early detection of breast cancer. To accomplish this, the study will use the resources of a study of over 14,000 healthy women between the ages of 35 and 65 who were enrolled at a breast cancer screening clinic and donated blood between 1985 and 1991. Since then, 1,006 invasive breast cancer cases have been diagnosed and for 113 of these cases blood samples were collected within 6 months prior to clinical diagnosis. This study will look at the gene promoter hypermethylation patterns in these 113 women and compare them to that of 226 healthy, cancer-free women. To date, no study has looked at these markers in the blood of women prior to breast cancer diagnosis, a necessary step in their evaluation as diagnostic tools. Early detection is an important determinant of breast cancer prognosis and survival. The proposed study will be the first to examine the promoter methylation patterns in the serum of women before breast cancer is diagnosed. It is hoped that through this research a new technique for early breast tumor detection may be developed.