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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.

Objective To ascertain whether D' Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort. Patients and Methods From family cancer pedigrees of patients evaluated through a familial breast cancer cohort all related men with a diagnosis of prostate cancer were identified. Genotyping of each patient or of the dominant familial BRCA2 mutation was undertaken in each instance. Prostate cancers were analysed by BRCA2 carrier vs non-carrier status for their clinical progression and survival according to their D'Amico risk groups. Results For patients who were BRCA2-mutation positive, there was no significant difference in cancer-specific survival ( CSS) between those patients who were graded as having D' Amico high- or intermediate-risk disease. For patients who were BRCA2-mutation negative, but were identified via a family cancer pedigree, there was no statistically significant difference in CSS between D' Amico high- and intermediate-risk prostate cancers. Patients with D' Amico high-risk disease who were BRCA2-mutation carriers had substantially increased disease-specific mortality compared with high-risk non-carriers (hazard ratio 2.94, P = 0.004). Conclusion D'Amico risk classification has limitations in predicting variations in prostate cancer-specific mortality for this group of patients. [ABSTRACT FROM AUTHOR]