BACKGROUND: One in six Australian men will be diagnosed with prostate cancer before the age of 75, however, only an unpredictable 10% will die of the disease. Recent research has focused on using genetic markers as tools for determining prostate cancer prognosis and the role of genetic translocation events in prostate cancer development. Translocations affecting biological processes may prove to have a predictive nature. Recently the DNA mismatch repair gene MSH2 has been shown to lose its function through a particular genetic translocation event. Whether this event is dependent upon androgens to occur and whether translocations in the MSH2 gene are a marker for poor prostate cancer outcome remains to be seen.
AIMS: This study aimed to show that translocations involving the MSH2 gene are induced by the androgens testosterone and dihydrotestosterone (DHT). In addition, this study attempted to determine the prevalence of MSH2 loss-of-function mutations in a patient cohort.
METHODS and RESULTS: A mutation in MSH2 was initially identified from whole genome sequencing of a cohort of 7 prostate cancer patients. Next a cohort of 117 high-risk and 90 low-risk prostate cancer patients was utilised to investigate the presence of the MSH2 protein by immunohistochemistry (IHC). 6 high-risk patients were found to have no staining for MSH2 whereas all low-risk patients stained for MSH2. Multiplex ligation-dependent probe amplification (MLPA), and a novel PCR based targeted sequencing assay were performed on a subset of patients from this larger cohort. These experiments identified copy number loss of MSH2 within the tumour of patients who had stained for the MSH2 protein on IHC, indicating that MSH2 loss could affect prostate tumour in a clonal nature. Furthermore we have developed a fluorescence in situ hybridisation assay to detect breaks in the MSH2 gene in patient samples and cell lines.