TY - JOUR
T1 - Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories
AU - Taylor, Renea A.
AU - Fraser, Michael
AU - Livingstone, Julie
AU - Espiritu, Shadrielle Melijah G.
AU - Thorne, Heather
AU - Huang, Vincent
AU - Lo, Winnie
AU - Shiah, Yu Jia
AU - Yamaguchi, Takafumi N.
AU - Sliwinski, Ania
AU - Horsburgh, Sheri
AU - Meng, Alice
AU - Heisler, Lawrence E.
AU - Yu, Nancy
AU - Yousif, Fouad
AU - Papargiris, Melissa
AU - Lawrence, Mitchell G.
AU - Timms, Lee
AU - Murphy, Declan G.
AU - Frydenberg, Mark
AU - Hopkins, Julia F.
AU - Bolton, Damien
AU - Clouston, David
AU - Mcpherson, John Douglas
AU - Van Der Kwast, Theodorus
AU - Boutros, Paul C.
AU - Risbridger, Gail P.
AU - Bristow, Robert G.
PY - 2017/1/9
Y1 - 2017/1/9
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85009062686&partnerID=8YFLogxK
U2 - 10.1038/ncomms13671
DO - 10.1038/ncomms13671
M3 - Article
C2 - 28067867
AN - SCOPUS:85009062686
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 13671
ER -