Patrick McCoy1,2, Stefano Mangiola3,4,5, Geoff Macintyre6,7, Ryan Hutchinson5,8, Ben Tran5,9, Bernard Pope10,11,12, Peter Georgeson10,13, Matthew K H Hong3, Natalie Kurganovs3,14,15, Sebastian Lunke8,16,17, Michael J Clarkson3, Marek Cmero3,5, Michael Kerger4, Ryan Stuchbery4, Ken Chow3, Izhak Haviv18, Andrew Ryan19, Anthony J Costello3,4, Niall M Corcoran3,20,21, Christopher M Hovens3,4. 1. Departments of Surgery and Urology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia. patrickjmccoy@bigpond.com. 2. Australian Prostate Cancer Research Centre, Melbourne, VIC, Australia. patrickjmccoy@bigpond.com. 3. Departments of Surgery and Urology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia. 4. Australian Prostate Cancer Research Centre, Melbourne, VIC, Australia. 5. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. 6. Statistics and Computational Biology Group, Cambridge, UK. 7. Department of Computing and Information Systems, University of Melbourne, Parkville, VIC, Australia. 8. Department of Pathology, University of Melbourne, Parkville, VIC, Australia. 9. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 10. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia. 11. Melbourne Bioinformatics, The University of Melbourne, Carlton, VIC, Australia. 12. Department of Medicine, Central Clinical School, Faculty of Medicine Nursing and Health Sciences, Monash University, Parkville, VIC, Australia. 13. Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia. 14. Ontario Institute for Cancer Research, Toronto, ON, Canada. 15. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 16. Murdoch Children's Research Institute, Melbourne, VIC, Australia. 17. Australian Genomics Health Alliance, Melbourne, VIC, Australia. 18. Faculty of Medicine in the Galilee, Bar Ilan University, Ramat Gan, Israel. 19. TissuPath Specialist Pathology, Mount Waverley, Melbourne, VIC, Australia. 20. Department of Urology, Frankston Hospital, Frankston, VIC, Australia. 21. The Victorian Comprehensive Cancer Centre, Parkville, VIC, Australia.
Abstract
BACKGROUND: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes. METHODS AND RESULTS: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours. CONCLUSIONS: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.
BACKGROUND: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes. METHODS AND RESULTS: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours. CONCLUSIONS: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.
Authors: Sylvan C Baca; Davide Prandi; Michael S Lawrence; Juan Miguel Mosquera; Alessandro Romanel; Yotam Drier; Kyung Park; Naoki Kitabayashi; Theresa Y MacDonald; Mahmoud Ghandi; Eliezer Van Allen; Gregory V Kryukov; Andrea Sboner; Jean-Philippe Theurillat; T David Soong; Elizabeth Nickerson; Daniel Auclair; Ashutosh Tewari; Himisha Beltran; Robert C Onofrio; Gunther Boysen; Candace Guiducci; Christopher E Barbieri; Kristian Cibulskis; Andrey Sivachenko; Scott L Carter; Gordon Saksena; Douglas Voet; Alex H Ramos; Wendy Winckler; Michelle Cipicchio; Kristin Ardlie; Philip W Kantoff; Michael F Berger; Stacey B Gabriel; Todd R Golub; Matthew Meyerson; Eric S Lander; Olivier Elemento; Gad Getz; Francesca Demichelis; Mark A Rubin; Levi A Garraway Journal: Cell Date: 2013-04-25 Impact factor: 41.582
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Authors: Victoria M Raymond; Bhramar Mukherjee; Fei Wang; Shu-Chen Huang; Elena M Stoffel; Fay Kastrinos; Sapna Syngal; Kathleen A Cooney; Stephen B Gruber Journal: J Clin Oncol Date: 2013-03-25 Impact factor: 44.544
Authors: Michael C Haffner; Martin J Aryee; Antoun Toubaji; David M Esopi; Roula Albadine; Bora Gurel; William B Isaacs; G Steven Bova; Wennuan Liu; Jianfeng Xu; Alan K Meeker; George Netto; Angelo M De Marzo; William G Nelson; Srinivasan Yegnasubramanian Journal: Nat Genet Date: 2010-07-04 Impact factor: 38.330
Authors: Chunru Lin; Liuqing Yang; Bogdan Tanasa; Kasey Hutt; Bong-gun Ju; Kenny Ohgi; Jie Zhang; David W Rose; Xiang-Dong Fu; Christopher K Glass; Michael G Rosenfeld Journal: Cell Date: 2009-12-11 Impact factor: 41.582