Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Renea A. Taylor, Michael Fraser, Julie Livingstone, Shadrielle Melijah G. Espiritu, Heather Thorne, Vincent Huang, Winnie Lo, Yu-Jia Shiah, Takafumi N. Yamaguchi, Ania Sliwinski, Sheri Horsburgh, Alice Meng, Lawrence E. Heisler, Nancy Yu, Fouad Yousif, Melissa Papargiris, Mitchell G. Lawrence, Lee Timms, Declan G. Murphy, Mark Frydenberg, Julia F. Hopkins, Damien Bolton, David Clouston, John D. McPherson, Theodorus van der Kwast, Paul C. Boutros (), Gail P. Risbridger () and Robert G. Bristow ()
Additional contact information
Renea A. Taylor: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Biomedicine Discovery Institute, Monash University
Michael Fraser: Princess Margaret Cancer Centre, University Health Network
Julie Livingstone: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Shadrielle Melijah G. Espiritu: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Heather Thorne: kConFab, Peter MacCallum Cancer Centre
Vincent Huang: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Winnie Lo: Princess Margaret Cancer Centre, University Health Network
Yu-Jia Shiah: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Takafumi N. Yamaguchi: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Ania Sliwinski: The Sir Peter MacCallum Department of Oncology University of Melbourne
Sheri Horsburgh: Princess Margaret Cancer Centre, University Health Network
Alice Meng: Princess Margaret Cancer Centre, University Health Network
Lawrence E. Heisler: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Nancy Yu: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Fouad Yousif: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Melissa Papargiris: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Monash University
Mitchell G. Lawrence: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Monash University
Lee Timms: Genome Technologies Program, Ontario Institute for Cancer Research
Declan G. Murphy: Peter MacCallum Cancer Centre
Mark Frydenberg: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Monash University
Julia F. Hopkins: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Damien Bolton: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Monash University
David Clouston: Urological Pathology, Tissupath
John D. McPherson: Genome Technologies Program, Ontario Institute for Cancer Research
Theodorus van der Kwast: Princess Margaret Cancer Centre, University Health Network
Paul C. Boutros: Informatics & Biocomputing Program, Ontario Institute for Cancer Research
Gail P. Risbridger: Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Monash University
Robert G. Bristow: Princess Margaret Cancer Centre, University Health Network

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

Date: 2017
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DOI: 10.1038/ncomms13671

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