Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

2017-01

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

Cancer genetics

Cancer genomics

Prostate cancer

Journal Article

0000-0002-5145-6783

10.1038/ncomms13671

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.

link

Nature Communications 2017; 8: 13671

Nature Communications