New Project: Novel epigenetic markers for toxicity after radiotherapy
Ionizing radiation is an efficient treatment in breast cancer therapy. However, some patients react to radiation with strong adverse side effects in the normal tissue which can severely limit the treatment's success (Popanda et al., 2009, Chang-Claude et al., 2009).
The individual radiosensitivity is a complex, polygenic trait including many pathways such as DNA repair, apoptosis or inflammatory response (Mayer et al., 2011). In this project, we hypothesize that the individual epigenetic pattern regulating gene expression and genomic stability will modulate the radiation response. The project is based on an ongoing study on 320 breast cancer patients receiving intraoperative radiotherapy (IORT). Recent follow-up of these patients showed that up to 25 % of patients develop moderate-severe fibrosis of the tumor bed within 3 years (Wenz et al., 2008).
The project will focus primarily on DNA methylation as an epigenetic mechanism and will
(i) identify whole genome methylation patterns in fibroblasts associated with cellular and clinical radiation hypersensitivity,
(ii) evaluate the DNA methylation status of repair genes in target cells (fibroblasts) with respect to cellular and individual radiation response,
(iii) characterize emerging candidate genes and the functional consequences of their methylation, and (iv) validate the new methylation markers in the cohort of IORT patients.
Special techniques applied will be a whole genome screening with enrichment of highly methylated DNA by the MCIp technique developed in our lab and next generation sequencing techniques as well as CpG island specific assays based on the MassArray Sequenom technology (Goeppert et al., 2010).
Finally, this translational project will identify new stable molecular markers which can be used to individualize and improve radiation therapy of breast cancer patients.
Open Position:
We are looking for a highly motivated, open-minded person with training in molecular and cellular biology. The candidate should have strong experimental skills and a special interest to work in close cooperation with the clinical partner.
In cooperation with Prof. Dr. Frederik Wenz, University Hospital, Mannheim, and Prof. Dr. Jenny Chang-Claude, Epidemiolgy DKFZ
References
Mayer C, Popanda O, Greve B, Fritz E, Illig T, Eckardt-Schupp F, Gomolka M, Benner A, Schmezer P. A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects. Cancer Lett. 302 (2011) 20-28.
F. Wenz, G. Welzel, A. Keller, E. Blank, F. Vorodi, C. Herskind, O. Tome, M. Sutterlin, U. Kraus-Tiefenbacher, Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer, Breast 17 (2008) 617-622.
J. Chang-Claude, C.B. Ambrosone, C. Lilla, S. Kropp, I. Helmbold, D. von Fournier, W. Haase, M.L. Sautter-Bihl, F. Wenz, P. Schmezer, O. Popanda, Genetic polymorphisms in DNA repair and damage response genes and late normal tissue complications of radiotherapy for breast cancer, Br. J. Cancer 100 (2009) 1680-1686.
Popanda O, Marquardt, JU, Chang-Claude J, Schmezer P. Genetic variation in normal tissue toxicity induced by ionizing radiation. Mutation Res, Fundamental Mol Mechanisms Mutagenesis 667:58-69, 2009.
Goeppert, B., Schmezer, P., Dutruel, C., Oakes, C., Renner, M., Breinig, M., Warth, A., Vogel, M.N., Mittelbronn, M., Mehrabi, A., Gdyna, G., Penzel, R., Longerich, T., Breuhahn, K., Popanda, O., Plass, C., Schirmacher, P., Kern, M.A. Downregulation of Tumor Suppressor A Kinase Anchor Protein 12 in Human Hepatocarcinogenesis by Epigenetic Mechanisms. Hepatology, 52(6), 2023-2033 (2010).
