The greatest challenge in the medical management of prostate cancer is the development of markers that can distinguish between early-stage, non-aggressive tumours and those that will progress to an invasive form of the disease. The major objective of the 'Genetic prostate cancer variants as biomarkers of disease progression' (PROMARK) project was to test if inherited genetic variants can serve as biomarkers for disease prognosis. The EU-funded project integrated the efforts of 18 research groups. During the course of the project samples and clinical information from 5 500 prostate cancer cases and over 7 000 controls from different parts of Europe were collected. Genetic studies of the collected samples led to the discovery of six sequence variants that affect the risk of prostate cancer. Only one of the variants showed a stronger association to the aggressive form of the disease. In addition, six sequence variants that associate with levels of prostate-specific antigen (PSA) in blood were identified. A risk model that included both the prostate cancer risk variants and PSA variants outperformed risk models that included only the cancer risk variants. Functional studies of the role of the transcription factor hepatocyte nuclear factor type 1Beta (HNF-1Beta) in normal and malignant prostate cells were performed. Expression analysis showed that higher levels of HNF-1Beta are associated with improved prognosis. Overexpression of HNF-1Beta in prostate cancer (PC3) cells demonstrated that HNF-1Beta has a measurable effect on the expression of a large number of genes. Pathway analyses indicated that the largest effect is on genes that play a role in cell death and survival, movement and proliferation. Overexpression of HNF-1Beta in PC3 cells reduced proliferation, adhesion, migration and colony formation in soft agar. Methylation studies showed that the HNF-1Beta promoter is differentially methylated in paired tumour and benign patient samples with a higher level of methylation in tumour cells. The results of the PROMARK project have been presented in 10 scientific publications. Patent applications have been filed for all prostate cancer and PSA sequence variants discovered in the project. The results from the functional analysis of HNF-1Beta may be used for the improved diagnosis and treatment of prostate cancer.
Genetic prostate cancer variants as biomarkers of disease progression
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