Abstract

Background

Several studies have reported the association of germline BRCA2
(gBRCA2) mutations with poor clinical outcomes in prostate cancer (PCa), but the impact of
concurrent somatic events on gBRCA2 carriers survival and disease progression is unknown.

Patients and methods

To ascertain the role of frequent somatic genomic alterations and
histology subtypes in the outcomes of gBRCA2 mutation carriers and non-carriers, we correlated the tumour characteristics and clinical outcomes of 73 gBRCA2 and 127 non-carriers.
Fluorescent in-situ hybridisation and next-generation sequencing were used to detect copy
number variations in BRCA2, RB1, MYC and PTEN. Presence of intraductal and cribriform
subtypes was also assessed. The independent impact of these events on cause-specific survival
(CSS), metastasis-free survival and time to castration-resistant disease was assessed using coxregression models.

Results

Somatic BRCA2-RB1 co-deletion (41% versus 12%, p < 0.001) and MYC amplification (53.4% versus 18.8%, p < 0.001) were enriched in gBRCA2 compared to sporadic
tumours. Median CSS from diagnosis of PCa was 9.1 versus 17.6 years in gBRCA2 carriers
and non-carriers, respectively (HR 2.12; p = 0.002), Median CSS in gBRCA2 carriers increased to 11.3 and 13.4 years in the absence of BRCA2-RB1 deletion or MYC amplification,
respectively. Median CSS of non-carriers decreased to 8 and 2.6 years if BRCA2-RB1 deletion
or MYC amplification were detected.

Conclusions

gBRCA2-related prostate tumours are enriched for aggressive genomic features,
such as BRCA2-RB1 co-deletion and MYC amplification. The presence or absence of these
events modify the outcomes of gBRCA2 carriers.