Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.

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.

• Authors: 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, Robert G Bristow
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 13671 (01 09 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28067867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA2 Protein
• BRCA2 protein, human
• MED12 protein, human
• Mediator Complex
• Protein Isoforms

Topics

• Aged
• BRCA2 Protein (deficiency, genetics)
• Carcinoma, Ductal (genetics, metabolism, pathology, surgery)
• DNA Mutational Analysis
• Epigenesis, Genetic
• Evolution, Molecular
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Genomic Instability
• Germ-Line Mutation
• Heterozygote
• Humans
• Male
• Mediator Complex (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Prostate (metabolism, pathology, surgery)
• Prostatectomy
• Prostatic Neoplasms (genetics, metabolism, pathology, surgery)
• Protein Isoforms (genetics, metabolism)
• Retrospective Studies
• Whole Genome Sequencing