Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16537
Title: Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories
Austin Authors: Taylor, Renea A;Fraser, Michael;Livingstone, Julie;Espiritu, Shadrielle Melijah G;Thorne, Heather;Huang, Vincent;Lo, Winnie;Shiah, Yu-Jia;Yamaguchi, Takafumi N;Sliwinski, Ania;Horsburgh, Sheri;Meng, Alice;Heisler, Lawrence E;Yu, Nancy;Yousif, Fouad;Papargiris, Melissa;Lawrence, Mitchell G;Timms, Lee;Murphy, Declan G;Frydenberg, Mark;Hopkins, Julia F;Bolton, Damien M ;Clouston, David;McPherson, John D;van der Kwast, Theodorus;Boutros, Paul C;Risbridger, Gail P;Bristow, Robert G
Affiliation: Monash Partners Comprehensive Cancer Consortium and Cancer Program, Biomedicine Discovery Institute, Department of Physiology, Monash University, Melbourne, Victoria, Australia
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
kConFab, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
The Sir Peter MacCallum Department of Oncology University of Melbourne, Parkville, Victoria, Australia
Department of Urology, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Monash Partners Comprehensive Cancer Consortium and Cancer Program Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
Department of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Urological Pathology, Tissupath, Mt Waverley, Victoria, Australia
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Department of Pharmacology &Toxicology, University of Toronto, Toronto, Ontario, Canada
Issue Date: Jan-2017
metadata.dc.date: 2017-01-09
Publication information: Nature Communications 2017; 8: 13671
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16537
DOI: 10.1038/ncomms13671
ORCID: 0000-0002-5145-6783
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/28067867
Type: Journal Article
Subjects: Cancer genetics
Cancer genomics
Prostate cancer
Appears in Collections:Journal articles

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