Several epidemiological studies that examined the risk of PCa among BRCA1
mutation carriers have suggested that protein-truncating BRCA2
mutations confer an increased risk of PCa, while the effect of mutations in the BRCA1
gene seems to be more modest (Leongamonlert et al.
, in press).23, 24, 51, 68, 69, 70, 71, 72, 73
However, one of the challenges of studies analysing the susceptibility of PCa in BRCA
mutation carriers is the low incidence of germline mutations in those genes in the general population which is estimated to be between 0.07% and 0.24% in different studies,72, 74, 75, 76
and therefore, results have often been inconsistent. The ethnic population that has more extensively been studied is the Ashkenazim Jewish, due to the relative high incidence of three founder mutations (BRCA1
5382insC and BRCA2
6174delT). It has been estimated that ~2% of this population carries at least one of these mutations.77, 78, 79, 80
Even in this population, the results of these epidemiological studies have been contradictory, but many of them were underpowered, due to small sample size or lack of covariate information.22, 81, 82, 83, 84, 85, 86
founder mutation that has been extensively studied is the Icelandic BRCA2
999del5 mutation. Johannesdottir et al.87
reported that this mutation was present in 2.7% of unselected Icelandic patients diagnosed with PCa at age ≤65 years. This prevalence is double the prevalence of germline BRCA2
mutations reported by Kote-Jarai et al.23
and Agalliu et al.22
in two cohorts of PCa patients diagnosed at age ≤65 years (1.2% and 0.78%, respectively).
In these latter two studies, patients were screened for any22
mutation, not only the founder ones.
To assess whether BRCA2
999del5 mutations contribute to PCa phenotype and prognosis, Tryggvadottir et al.64
analysed a group of 89 PCa patients diagnosed in Iceland between 1955 and 2004. The study included 30 men carrying the Icelandic founder mutation, and for each carrier, two control patients without the mutation. Compared with non-carriers, the mutation carriers were younger at diagnosis (69 years vs.
74 years); presented with more advanced tumour stage (T) (T3–4: 79% vs.
36%) and poorly differentiated tumours (84% vs.
52.7%). Median cause-specific survival (CSS) for carriers was 2.1 years compared with 12.4 years for non-carriers.
After Tryggvadottir et al.64
suggested that BRCA
mutations could have clinical implications beyond increasing the risk of PCa, another two studies analysed the role of a wide spectrum of mutations in BRCA2.
None of them included patients with the Icelandic founder mutation. Edwards et al.88
compared overall survival (OS) after PCa diagnosis in a series of 21 BRCA2
mutation carriers and 1587 controls, 263 of which had tested negative for BRCA2
mutations. Carriers had a median OS of only 4.8 years compared with 8.5 years for the non-carriers. More recently, Thorne et al.89
reported the analysis of the outcome of PCa in 40 BRCA2
mutation carriers compared with 97 BRCA
wild-type patients. Non-carriers belonged to families with a history of breast cancer. No difference in age or PSA at diagnosis between carriers and non-carriers was seen. BRCA2
carriers presented with less differentiated (65.8% vs.
33%) and larger (T≥3) tumours (39.5% vs.
22.6%) than non-carriers. Despite 79% of patients in both groups (carriers and non-carriers), receiving similar local treatment with curative intent, those with BRCA2
mutations had a worse CSS. BRCA2
mutation status was shown to be an independent predictor of CSS (hazard ratio (HR): 4.97; 95% confidence interval (CI): 2.19–11.25). Interestingly, the non-carrier group also had a poorer outcome compared with other series of sporadic PCa, suggesting that a family history of breast cancer might, somehow, affect the prognosis of PCa patients.
Two studies have analysed the implications of both BRCA1
mutations. Narod et al.90
reported a series of 67 BRCA2
and 37 BRCA1
mutation carriers or obligate carriers of different BRCA
mutations. The study analysed the prognosis of BRCA1 vs. BRCA2
mutation carriers and did not include a BRCA
wild-type group for comparison. No information was available on pathology or clinical features of the PCa cases. They observed that the 5-year OS for all causes of death was shorter for BRCA2
than for BRCA1
64%, respectively) with a median OS of 15 years for BRCA1
mutation carriers and 5 years for BRCA2
mutation carriers. Gallagher et al.65
reported a series that included 26 PCa cases carrying the Ashkenazi founder mutations BRCA2
6174delT (20 men) and BRCA1
185delAG (6 men), and 806 non-carriers. All patients presented with early-stage PCa were screened for the two mutations. Patients carrying BRCA2
6174delT presented with poorly differentiated tumours more frequently than non-carriers (85% vs
. 57%). No association with the tumour phenotype was observed for BRCA1
185delAG. Both mutations conferred a higher risk of biochemical relapse and metastasis. CSS was 19.1 years for non-carriers compared with 13 and 12.5 years for BRCA1
185delAG and BRCA2
6174delT, respectively. Although these results should be assessed cautiously due to the sample size, both mutations were found to be predictors of poorer CSS (HR: 5.16; 95% CI: 1.09–24.53; and HR: 5.48; 95% CI: 2.03–14.79, for BRCA1
mutation carriers, respectively). In general, these previous series were limited when analysing patient outcomes, due to the small number of BRCA
mutation carriers with little clinical information, or to the lack of a comprehensive multivariate analysis. Thus, the real independent prognostic contribution of BRCA
mutations might be overestimated, compared with other classical prognostic factors for PCa outcome. In an attempt to better understand the implications of BRCA1
germline mutations, we have recently reported the analysis of 2019 PCa patients, 18 and 61 of them harbouring BRCA1
germline mutations, respectively.63
This is the largest study to date investigating the clinical characteristics and outcome of PCa patients with and without BRCA
mutations. Our results reveal that a wide spectrum of pathogenic mutations in the BRCA1
genes confers a more aggressive PCa phenotype and these tumours are more frequently associated with lymph node involvement and distant metastasis at diagnosis than PCa in non-carriers. We have not seen differences in age at diagnosis as previously reported by others.65, 84, 89, 91
This contradicts Tryggvadottir's observations,64
but our study63
did not include any patients with the Icelandic founder mutation BRCA2
999del5, and we cannot exclude that some mutations are associated with younger age at diagnosis. BRCA1
carriers had a higher incidence of poorly differentiated tumours, presented with larger tumours and a higher incidence of node involvement and distant metastasis. We have also demonstrated that BRCA
germline mutations in PCa, particularly in the BRCA2
gene, are associated with poor OS and CSS independently of other classical prognostic factors, including stage, Gleason score and PSA.