Journal Article

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

Lo, Winnie, Lawrence, Mitchell G., McPherson, John D., Bristow, Robert G., Boutros, Paul C., Espiritu, Shadrielle Melijah G., Frydenberg, Mark, Huang, Vincent, Timms, Lee, Yousif, Fouad, Clouston, David, Heisler, Lawrence E., Yu, Nancy, Yamaguchi, Takafumi N., Taylor, Renea A., Meng, Alice, Horsburgh, Sheri, Hopkins, Julia F., van der Kwast, Theodorus, Thorne, Heather, Fraser, Michael, Shiah, Yu-Jia, Murphy, Declan G., Bolton, Damien, Risbridger, Gail P., Livingstone, Julie, Papargiris, Melissa, Sliwinski, Ania

2017

Overview

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. Men that carrier BRCA2 germline mutations are at risk of developing prostate cancer. Here, the authors analyse the genomes of prostate cancer from these individuals and demonstrate increased genomic instability in comparison to sporadic prostate cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208/68 / 631/67/69 / 692/4028/67/589/466 / Aged / BRCA2 Protein - deficiency / BRCA2 Protein - genetics / Breast cancer / Cancer research / Carcinoma, Ductal - genetics / Carcinoma, Ductal - metabolism / Carcinoma, Ductal - pathology / Carcinoma, Ductal - surgery / Consortia / DNA Mutational Analysis / Epigenesis, Genetic / Evolution, Molecular / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes / Genetic Predisposition to Disease / Genomes / Genomic Instability / Germ-Line Mutation / Heterozygote / Humanities and Social Sciences / Humans / Male / Mediator Complex - genetics / Mediator Complex - metabolism / Medical research / Metastasis / Middle Aged / multidisciplinary / Mutants / Mutation / Neoplasm Invasiveness / Prostate - metabolism / Prostate - pathology / Prostate - surgery / Prostate cancer / Prostatectomy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Prostatic Neoplasms - surgery / Protein Isoforms - genetics / Protein Isoforms - metabolism / Retrospective Studies / Science / Science (multidisciplinary) / Tumors / Whole Genome Sequencing