Analysis of epigenetic markers for a stratification of patients

Coordinator:    Dr. Jörg Hoheisel
Institution: DKFZ Heidelberg
The major objective of this subproject is the use of a set of epigenetic markers for a stratification of patients prior to therapy and an evaluation of the patients' response to treatment. In the beginning, a set of about 500 genes will be analysed in detail with respect to their epigenetic pattern in their promoter region. One focus area will be the analysis of microRNA gene promoters, representing a higher hierarchical level of regulation. Both, primary samples taken from tumour biopsies as well as serum samples will be analysed. Follow-up information for the patients is documenting the success/failure of different adjuvant therapy protocols. Second, tissue and serum samples will be available from patients that underwent palliative surgery and subsequent therapy. Follow-up data of these patients is also available, documenting the success/failure of different palliative therapies. It provides the opportunity to analyse treatment response in this context. The analysis is based on a bisulfite treatment of the genomic DNA. Bisulfite converts unmethylated cytosines into uracil and upon PCR into thymine. Methylated cytosine, however, are unaffected. Therefore, methylation variations can be analysed as sequence variations. For the superior stability of DNA compared to RNA and the lack of artificial variation during sample preparation, epigenetic variations are a superior and more reproducible means for diagnosis resulting in a much better accuracy of calling variations. In addition to the analysis of human material, we will perform comparative studies between the mouse models and human samples in order to identify similar processes and thereby validate the relevance of the animal model for the situation in human. The human material will be used to define and validate markers predicting/monitoring treatment success in both the adjuvant and palliative setting. The mouse models will be utilized to integrate and validate the knowledge from human tissue/serum, and to provide a platform to efficiently test novel therapeutic strategies.
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