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MSH2 is Inactivated by Multiple Mechanisms in Prostate Tumors, Leading to a Distinct Immune Response and Clinical Outcome Compared to MSH2 Deficient Colorectal Cancer

45 Pages Posted: 10 Sep 2018 Publication Status: Under Review

See all articles by Patrick McCoy

Patrick McCoy

University of Melbourne - Department of Surgery

Stefano Mangiola

Australian Prostate Cancer Research Centre Epworth

Geoff Macintyre

Statistics and Computational Biology Group

Ryan Hutchinson

The Walter and Eliza Hall Institute of Medical Research

Ben Tran

The Walter and Eliza Hall Institute of Medical Research

Matthew KH Hong

University of Melbourne - Department of Surgery

Natalie Kurganovs

University of Melbourne - Department of Surgery

Michael J. Clarkson

University of Melbourne - Department of Surgery

Marek Cmero

University of Melbourne - Department of Surgery

Michael Kerger

Australian Prostate Cancer Research Centre Epworth

Ryan Stuchbery

Australian Prostate Cancer Research Centre Epworth

Ken Chow

University of Melbourne - Department of Surgery

Izhak Haviv

University of Melbourne - Royal Melbourne Hospital

Andrew Ryan

TissuPath Specialist Pathology

Anthony J. Costello

Australian Prostate Cancer Research Centre Epworth

Niall M. Corcoran

Australian Prostate Cancer Research Centre Epworth

Christopher M. Hovens

Australian Prostate Cancer Research Centre Epworth

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Abstract

Patients with defects in the mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer, whilst germline MMR defects in either MLH1 or PMS2, exhibit no such increase. Prostatic carcinogenesis is driven by androgen signalling. Here we show that androgen-receptor activation can disrupt the MSH2 gene in prostate cancer model systems. We screened tumors from two contrasting risk cohorts of prostate cancer patients to confirm loss of MSH2 protein expression and surprisingly found a small but significant fraction of high risk cases exhibited reduced expression of MSH2. Stratifying a large independent TCGA prostate cancer cohort for MSH2 expression levels revealed that patients whose tumors exhibited either complete loss or aberrant levels of MSH2 had equally significant worse survival outcomes and accelerated clinical progression. In contrast, colorectal cancer patients with aberrant MSH2 levels had improved clinical survival. We show that reduced expression of MSH2 can also occur through androgen-induced miRNA regulatory mechanisms. Aberrant MSH2 expression in prostate tumors does not induce enhanced immune cell mobilisation seen in colorectal tumors suggesting that the prostate is an immune privileged site that is less likely to benefit from immunotherapies.

Suggested Citation

McCoy, Patrick and Mangiola, Stefano and Macintyre, Geoff and Hutchinson, Ryan and Tran, Ben and Hong, Matthew KH and Kurganovs, Natalie and Clarkson, Michael J. and Cmero, Marek and Kerger, Michael and Stuchbery, Ryan and Chow, Ken and Haviv, Izhak and Ryan, Andrew and Costello, Anthony J. and Corcoran, Niall M. and Hovens, Christopher M., MSH2 is Inactivated by Multiple Mechanisms in Prostate Tumors, Leading to a Distinct Immune Response and Clinical Outcome Compared to MSH2 Deficient Colorectal Cancer (September 6, 2018). Available at SSRN: https://ssrn.com/abstract=3245216 or http://dx.doi.org/10.2139/ssrn.3245216
This version of the paper has not been formally peer reviewed.

Patrick McCoy (Contact Author)

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Stefano Mangiola

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

Geoff Macintyre

Statistics and Computational Biology Group

Cambridge
United Kingdom

Ryan Hutchinson

The Walter and Eliza Hall Institute of Medical Research

1G Royal Pde
Parkville, Victoria 3052
Australia

Ben Tran

The Walter and Eliza Hall Institute of Medical Research

1G Royal Pde
Parkville, Victoria 3052
Australia

Matthew KH Hong

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Natalie Kurganovs

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Michael J. Clarkson

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Marek Cmero

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Michael Kerger

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

Ryan Stuchbery

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

Ken Chow

University of Melbourne - Department of Surgery

185 Pelham Street
Carlton, Victoria 3053
Australia

Izhak Haviv

University of Melbourne - Royal Melbourne Hospital

300 Grattan St
Parkville, Victoria 3050
Australia

Andrew Ryan

TissuPath Specialist Pathology

96 Ricketts Road
Mount Waverley, VIC 3149
Australia

Anthony J. Costello

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

Niall M. Corcoran

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

Christopher M. Hovens

Australian Prostate Cancer Research Centre Epworth

14-20 Blackwood St
North Melbourne VIC 3195
Australia

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