What germline mutation is associated with an increased risk of early onset high-grade prostate cancer?

BRCA2 Germline Mutation is Associated with Early Onset High-Grade Prostate Cancer

BRCA2 germline mutations are most strongly associated with an increased risk of early onset high-grade prostate cancer, conferring a 2-6 fold increased risk compared to non-carriers. 1

Genetic Mutations and Prostate Cancer Risk

BRCA2 Mutations

BRCA2 mutations have the strongest evidence for association with early onset and aggressive prostate cancer:

• Found in approximately 5.3% of metastatic prostate cancer cases 1
• Associated with a 2-6 fold increased risk of prostate cancer 2, 1
• Prostate cancer in BRCA2 carriers demonstrates more aggressive phenotypes and significantly reduced survival times compared to non-carriers 2
• Men with BRCA2 mutations and PSA >3.0 ng/mL have a significantly higher positive predictive value for detecting intermediate/high-grade cancer (2.4% vs 0.7% in controls) 2, 1

Other Relevant Germline Mutations

While BRCA2 has the strongest association, other germline mutations also increase prostate cancer risk:

• BRCA1 mutations: Less consistently associated with prostate cancer risk compared to BRCA2 2, 3
• HOXB13 mutations: Associated with hereditary prostate cancer 2, 4
• DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2): Associated with Lynch syndrome and confer a 2-5 fold increased risk of prostate cancer 2, 1
• ATM mutations: Found in 1.6% of metastatic prostate cancer cases and associated with aggressive disease 1, 4
• CHEK2 mutations: Found in 1.9% of metastatic prostate cancer cases 1, 4

Clinical Implications

Screening Recommendations

• NCCN Guidelines recommend prostate cancer screening beginning at age 40 for BRCA2 mutation carriers 2, 1
• Consider prostate cancer screening for BRCA1 carriers 2
• HOXB13 mutation status should be factored into prostate cancer screening discussions 2
• Annual PSA screening or screening determined by baseline PSA is recommended for those with germline mutations 2

Management Considerations

• Men with BRCA2 mutations should not be managed with active surveillance due to the aggressive nature of their disease 1
• BRCA2 mutation status should be factored into management discussions for early-stage/localized prostate cancer (64% consensus) and high-risk/advanced prostate cancer (97% consensus) 2
• Genetic testing should be considered for men with metastatic prostate cancer, as results may impact treatment options 2, 5, 6

Important Caveats and Considerations

1. Family History Limitations: Relying solely on family history for risk assessment is insufficient, as only 45.5% of mutation carriers have mutations concordant with personal and family history 1

2. Ethnic Variations: Ashkenazi Jewish men have higher carrier rates of BRCA1/2 mutations (>2%) and a 16% chance of developing prostate cancer by age 70 if they carry these mutations 1

3. Multiple Primary Cancers: Men with prostate cancer and at least one additional primary cancer have a higher likelihood (10.8%) of harboring germline mutations in cancer-predisposing genes 7

4. Cascade Testing: Identifying germline mutations in prostate cancer patients enables cascade testing of family members, which can have an impact extending beyond the index patient 6

While several germline mutations increase prostate cancer risk, BRCA2 mutations have the strongest and most consistent association with early onset high-grade prostate cancer and should be prioritized in genetic testing for men with this clinical presentation.