Poster Presentation & Flash Talk Presentation 29th Lorne Cancer Conference 2017

The potential of androgen driven disruption to the mismatch repair gene Msh2 in Prostate Cancer (#32)

Patrick McCoy 1 2 3 , Geoff Macintyre 4 , Michael Clarkson 1 3 5 , Natalie Kurganovs 1 3 5 , Andrew Ryan 6 , Sebastian Lunke 7 8 , Marek Cmero 4 9 , Jessica Chung 10 , Stefano Mangiola 4 9 , Clare Sloggett 10 , Niall Corcoran 1 4 5 , Chris Hovens 1 4 5
  1. Australian Prostate Cancer Research Centre Epworth, Melbourne, Victoria, Australia
  2. Royal Melbourne hospital, Parkville, VIC, Australia
  3. Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
  4. University of Melbourne, Melbourne, Victoria, Australia
  5. Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
  6. Tissupath Specialist Pathology Services, Melbourne, Victoria, Australia
  7. Centre for Translational Pathology, University of Melbourne, Melbourne
  8. Murdoch Childrens Research Institute, Melbourne, VIC, Australia
  9. walter and eliza hall institute, Melbourne, VIC, Australia
  10. victorian life sciences supercomputing, Melbourne

BACKGROUND: Lynch Syndrome is the most common hereditary cancer disorder and is caused by a defect in one of four DNA mismatch repair genes (MSH2, MLH1, PMS2 and MSH6). Prostate cancer has not commonly been associated with Lynch Syndrome but recent studies have identified that patients with a defect in the MSH2 gene have a significantly higher chance of developing prostate cancer. This increased prevalence however, is not observed in patients who have a defect in MLH1, PMS2 or MSH6. In this study we investigated the loss of MSH2 function by chromosomal translocations or post-transcriptional regulation by microRNAs and its effect on prostate cancer progression.

AIM: To identify hormonally regulated mechanisms for disruption of the MSH2 gene in prostate cancer and investigate their potential as prognostic tools in prostate cancer.

METHODS and RESULTS: From 7 prostate cancer patients who were selected for whole genome sequencing, MSH2 was found to be lost in one patient due to a gene fusion event. A cohort of 98 recurrent and 90 non-recurrent prostate cancer patients were investigated by immunohistochemistry to identify if MSH2 loss was consistent in a subpopulation of prostate cancers. 4 recurrent patients were found to have no staining whereas all non-recurrent patients showed staining. Additionally, 24 recurrent patients and 9 non-recurrent patients were observed to have weak MSH2 staining. A break-apart fluorescence in-situ hybridisation (FISH) assay was applied to identify MSH2 translocations in low/negative MSH2 patient samples, identifying 7 patients with translocations in the MSH2 gene. We also used this FISH assay to investigate the effect of androgens on the frequency of breaks in the MSH2 gene in LAPC4, PC3 and VCAP cell lines. MicroRNAs have also been implicated in the regulation of DNA repair genes, hence we performed an in silico screen to identify target microRNAs. MiR-21, mir-141 and miR-212 were identified as potential regulators of MSH2 and confirmed by western blot analysis. QPCR was performed to identify the patient expression profiles and hormonal regulation.

CONCLUSION: This study has successfully identified a subpopulation of prostate cancers with low MSH2 expression and has illustrated that this phenotype is associated with recurrence.