DNA Methylation Markers to Early Detect Breast Cancer

Breast cancer is by far the most common cancer with a one in 8-9 chance of women for developing this disease. The concept of early detection - finding tumors early, before they spread and become incurable - represents one of the most promising approaches to reducing the growing cancer burden. In recent years much evidence has accumulated to show that alterations in the patterns of methylation of CpG dinucleotides, particularly de novo methylation of CpG islands, are very common in all types of human cancer. In this application we propose to use the detection of aberrant patterns of DNA methylation in serum and Nipple Aspirate Fluid (NAF) to detect breast cancer early. We propose to use a sophisticated, automated high-throughput methylation analysis technology called MethyLight. The use of tumor-specific methylated DNA in serum and NAF poses many potential advantages over alternative strategies (sensitivity, specificity, stability of DNA, positive signal, automated and objective analysis, etc.). This extensive study is planned from the start as a multidisciplinary approach involving all members of our "Tyrolean Breast Cancer Care Unit" (radiologists, gynecologists, molecular biologists, pathologists and biostatisticians). The preliminary data provided in this proposal clearly demonstrate the feasibility of this three-year study: DNA methylation can be analyzed in any of the described body fluids using a high-throughput system. The strategies used to handle the huge volume of samples and data obtained on this project and the proposed steps (gene preselection, gene evaluation, training and test sets) that will subsequently define a small panel of genes able to detect breast cancer early, are described. Assuming that even in the test set, DNA methylation markers in serum and/or NAF are able to predict whether a patient has breast cancer, these analyses will be extended to samples collected from women at high risk of developing breast cancer during surveillance visits. The lag time between screen positivity based on DNA methylation markers and on tests conducted in the routine surveillance of high-risk patients will then be calculated. A simple, harmless and objective high-throughput screening tool for the entire female population will lay the groundwork for preselecting patients, who can then profit from modern techniques like image fusion. This study is intended as a first step toward ultimately eliminating advanced breast cancers by means of early detetction of cancers that can be removed by minimally invasive interventions.