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Evaluation of epigenetic biomarkers in prostate cancer patients before and after hormone ablation therapy

Final Report Summary - EPIGENETIC MARKER (Evaluation of epigenetic biomarkers in prostate cancer patients before and after hormone ablation therapy)

Prostate cancer is the second leading cause of death among men in Western countries. Various risk factors such as age, race, family history or dietary and environmental factors have been associated with prostate cancer development implicating involvement of both genetic and epigenetic factors. The heterogeneous nature of prostate cancer and the lack of defined biomarkers make it difficult to predict the behavior of a tumor and its response to different therapeutic approaches. Although hormone ablation therapies show initial effects, most tumors relapse as hormone-independent cancers and the disease can progresses and recur as aggressive metastases. It is still unclear which molecular mechanisms are driving this progression from hormone dependent into hormone insensitive cancer.

In the current project we aimed to investigate the clinical relevance of DNA hypermethylation and Polycomb protein expression in patient samples of prostate cancer patients before and after hormone ablation therapy. Furthermore, we tested our previous results obtained in prostate cancer cell lines by using biopsies and paraffin embedded tissues from cancer patients, to learn more about the clinical significance of epigenetic mechanisms in prostate cancer.

Immunohistochemical analyses of tissue arrays made from untreated and treated patient tumors, PIN and adjacent normal tissue showed a tumor specific increase in the levels of DNA methyltransferases and the histone methyltransferase EZH2. Interestingly, decreased staining of DNMTs and EZH2 was observed in some tumors shortly after hormone ablation therapy. Furthermore, we frequently detected aberrant DNA methylation in malignant tissues isolated from untreated, hormone ablated and hormone insensitive tumors as compared to normal prostate tissue or PBMC DNA. Interestingly, the pattern of methylation was similar for all different groups (untreated, treated, insensitive), albeit we found generally higher levels of methylation in hormone refractory prostate cancers as compared to untreated and treated specimens for individual genes. This cancer specific signature of DNA methylation might be useful for prostate cancer detection or follow-up.

Using genome-scale DNA methylation analyses on primary prostate cancer and adjacent normal tissues we identified a 18 gene signature, which enabled robust classification of tumor samples. One hypermethylated target was analysed in more detail on protein level and emerged as a suitable marker for differentiation between normal and malignant tissues in archived paraffin prostate cancer tissues.

We are planning on further evaluating the tumor specific signature in urine samples from prostate cancer patients to test for their application as non-invasive tumor markers in a follow up project. Our data will be important to establish molecular biomarkers for prostate cancer detection, and to elucidate the molecular mechanisms involved in the loss of hormone dependency in prostate cancer, which will have implications in therapy selection and identification of novel predictive biomarkers in the future.