Germline Mutation Associated with Early Onset High-Grade Prostate Cancer
The germline mutation most strongly associated with an increased incidence of early onset high-grade prostate cancer is BRCA2. 1
Evidence for BRCA2 as the Primary Mutation
BRCA2 germline mutations confer the highest known genetic risk for prostate cancer, with the following key characteristics:
- 2-6 fold increased risk of prostate cancer compared to non-carriers 2, 1
- More aggressive phenotype with significantly reduced survival times 2, 1, 3
- 5.3% prevalence in men with metastatic prostate cancer 1
- 23-fold increased relative risk of developing prostate cancer by age 56 4
- Particularly associated with early-onset disease 4
- Stronger association with high-grade (Gleason score ≥7) prostate cancer (SIR 5.07) than low-grade disease (SIR 3.03) 5
- Higher risk of death from prostate cancer (SMR 3.85) 5
Comparison with Other Germline Mutations
BRCA1
- Less consistent association with prostate cancer risk than BRCA2 2, 1
- Found in only 0.9% of metastatic prostate cancer cases 1
- Shows some association with early-onset disease but significantly weaker than BRCA2 2
HOXB13
- Not specifically mentioned in the provided evidence as a major contributor to early-onset high-grade prostate cancer
P53
- Not identified in the evidence as a significant contributor to early-onset high-grade prostate cancer
MSH2 (and other Lynch syndrome genes)
- Confer a 2-5 fold increased risk of prostate cancer 1
- Unlike BRCA2, Lynch syndrome genes do not typically present with earlier onset or more aggressive phenotype 1
Clinical Implications
The IMPACT study demonstrated that BRCA2 carriers with PSA >3.0 ng/mL had a significantly higher positive predictive value for detecting intermediate/high-grade cancer (2.4% vs 0.7% in controls) 2, 6.
Men with BRCA2 mutations should not be managed with active surveillance as they have more aggressive disease 3. The NCCN Guidelines recommend that men with BRCA2 mutations begin prostate cancer screening at age 40 2.
Mutation Location Significance
Interestingly, the location of BRCA2 mutations affects risk levels. Mutations in the region bounded by positions c.2831 and c.6401 are associated with lower prostate cancer risk (HR 0.37) compared to mutations outside this region 5.
In conclusion, while several germline mutations are associated with increased prostate cancer risk, BRCA2 has the strongest and most consistent association with early-onset high-grade prostate cancer based on the available evidence.