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

BRCA2 Germline Mutation and Early Onset High-Grade Prostate Cancer

BRCA2 germline mutation is the primary genetic alteration associated with an increased incidence of early onset high-grade prostate cancer, conferring a 2-6 fold increased risk with more aggressive phenotype and significantly reduced survival times. 1

Evidence for BRCA2 as the Primary Mutation

BRCA2 mutations have the strongest association with early onset, aggressive prostate cancer among all germline mutations:

• BRCA2 mutations are found in 5.3% of men with metastatic prostate cancer, making it the most common germline mutation in this population 2, 1
• Men with BRCA2 mutations have an 8.6-fold increased risk of developing prostate cancer by age 65 3
• The absolute risk of prostate cancer by age 65 for BRCA2 carriers is approximately 15%, increasing to 27% by age 75 and 60% by age 85 4
• BRCA2 carriers have a median survival of 4.8 years compared to 8.5 years in non-carriers, indicating significantly worse outcomes 5

Characteristics of BRCA2-Associated Prostate Cancer

BRCA2-associated prostate cancer has distinct clinical features:

• More aggressive disease phenotype with higher Gleason scores (SIR 5.07 for Gleason ≥7 vs. SIR 3.03 for Gleason ≤6) 4
• Earlier age of onset, with all carriers of truncating mutations developing prostate cancer at ≤65 years in one study 3
• Higher mortality rate (SMR 3.85) compared to non-carriers 4
• Not suitable for active surveillance due to aggressive nature 1

Other Relevant Germline Mutations

While BRCA2 is the predominant mutation, other DNA repair gene mutations are also associated with prostate cancer risk:

• ATM (1.6% of metastatic cases) 2, 1
• CHEK2 (1.9% of metastatic cases) 2, 1
• BRCA1 (0.9% of metastatic cases) - less consistent association than BRCA2 2, 1
• Less common mutations include PALB2, RAD51D, ATR, NBN, PMS2, and others (each <0.5% of metastatic cases) 2

Clinical Implications

The identification of BRCA2 mutations has important clinical implications:

• Earlier screening is recommended - NCCN guidelines recommend prostate cancer screening beginning at age 40 for BRCA2 mutation carriers 1
• Genetic testing should be considered for men with early-onset prostate cancer, as approximately 2.3% of men diagnosed ≤55 years harbor BRCA2 mutations 6
• Family history alone is insufficient for risk assessment, as only 45.5% of mutation carriers have mutations concordant with personal and family history 1
• Special attention should be given to Ashkenazi Jewish men, who 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 2, 1

Pitfalls and Caveats

• Relying solely on family history of prostate cancer may miss many BRCA2 mutation carriers
• BRCA2 mutations outside the region bounded by positions c.2831 and c.6401 confer higher prostate cancer risk than mutations within this region 4
• The association between BRCA1 mutations and prostate cancer is less consistent and may be influenced by screening effects 4
• Approximately 11.8% of men with metastatic prostate cancer have germline mutations in DNA repair genes, highlighting the importance of comprehensive genetic testing rather than testing for BRCA2 alone 2