DNA methylation and breast cancer

Breast cancer is the most common cancer among women in the USA as well as in Europe. Despite intensive research, there are only few parameters available who are able to judge whether a patient will be cured after therapy or would need a different type of treatment. During the last decade much evidence has accumulated showing that alterations in the patterns of methylation of CpG dinucleotides, particularly de novo methylation of CpG islands, are very common in human cancer, including breast cancer. These tumor-specific alterations can be detected in the serum of the corresponding patient. We propose to use a sophisticated high throughput methylation analysis technology called MethyLight, to identify methylation patterns which are specific for breast cancer compared to non-neoplastic breast tissue. We also plan to correlate methylation of genes in breast cancer with clinicopathological features (histology, stage, grade, etc.) as well as with relapse-free survival and overall survival. In addition, we shall study methylation of genes which are frequently methylated in breast cancer and never methylated in white blood cells or endothelial cells, in preoperative sera of patients diagnosed with breast cancer as well as in patients diagnosed with benign diseases of the breast or in healthy probands. We can then evaluate whether presence of a specific tumor-specific methylated gene present in preoperative serum is associated with clinical outcome of the patient. Finally, we propose to use the most promising biomarkers to evaluate the capacity to detect preclinical relapse of disease, as a function of time before clinical diagnosis of relapse. At our Department a very extensive breast cancer tissue bank and serum collection has been maintained since 1989. Not only were samples stored from breast cancer patients, but a total of more than 13.000 serially collected serum samples from these same patients has also been archived. Due to the fact that almost all patients had follow up at our Department, the median follow up is 6-7 years. This extensive study is planned to be conducted as a multidisciplinary approach involving gynecologic oncologist, molecular biologists, pathologists as well as epidemiologists and statisticians.Up to now, the preliminary data provided within this proposal is by far the most extensive methylation study within breast cancer. Combining this technology with the extensive specimen and serum collection, wed like to be able not only to better understand this very frequent disease but also to receive tools to predict clinical response to treatment as well as to detect this disease at an early stage. This kind of proposed methylation analysis might not only influence the breast cancer field but all types of malignancies.

Cancer exacts a tremendous toll on society. In addition to the devastating effects on patients and their families, the economic costs of breast cancer are enormous, both in terms of direct medical-care resources for its treatment and the loss of human capital due to early mortality. The concept of (1) early detection (finding tumors early, before they spread and become incurable) and (2) individualization of treatment, 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 project we used the detection of aberrant patterns of DNA methylation in tissue and serum to identify markers that (1) allow early detection of breast cancer, (2) add prognostic information and (3) acts as predictive markers. Within the scope of this project, a total of 18 papers (Impact factor > 100) has been published. Numerous presentations have been given and first authors have been awarded prestigious prizes. The project`s success was mainly due to three reasons: (1) the support by the Austrian FWF the luck I had to meet people who had been enthusiastic about the idea to make a real change in women with breast cancer, (2) the infrastructure provided by the TILAK GesmbH and (3) the luck I had to meet people who had been enthusiastic about the idea to make a real change in women with breast cancer.