Biological and clinical significance of micro-amplifications in prostate cancer

Coordinator:    PD Dr. Ronald Simon
Institution: Institut für Pathologie
The pathological increase of gene copy number (amplification) in cancer cells represents an important mechanism for the activation of oncogenes by overexpression. Although amplicons may encompass large chromosomal segments including multiple genes, only one of these genes has a crucial role in tumor biology in most cases. Massive overexpression of this important gene is the driving force that ultimately conveys a selection advantage to the tumor cells, so that these „driver“ genes represent promizing candidates for the development of new targeted therapies for cancer management.
The project aims in the discovery of new amplified genes with clinical relevance for prostate cancer. In a first step, we perform whole genome DNA copy number profiling in clinical prostate cancer specimens using high-resolution SNP arrays in order to find chromosomal segments undergoing high-level amplification. Small amplicons containing only few genes are of particular interest because the likelihood to find the relevant driver gene is the higher the less genes are involved. In addition, a special software tool combining SNP and other available data (e.g. expression level or gene function) is employed for further target prioritization. In a second step, amplification of the putative candidate driver genes is validated by fluorescence in-situ hybridization (FISH) analysis of more than 2,500 tissue samples of prostata cancer specimens in a tissue microarray (TMA) format. Comparison of the molecular findings with histo-pathological features of the arrayed cancer samples and the clinical follow-up data allows for estimation of the clinical impact of the candidate gene. In a last step we will perform functional analysis of promizing candidate genes in cell line models. A tissue microarray with more than 120 different human cancer cell lines is available in order to quickly identify suitable cell lines characterized by amplification of the driver gene. The project will serve as a basis for the development of new drugs for targeted therapy of prostate cancer.   
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