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

BRCA2 Germline Mutation Is Most Strongly Associated with Early-Onset High-Grade Prostate Cancer

BRCA2 germline mutation is the most strongly associated genetic alteration with early-onset high-grade prostate cancer, conferring a 2-6 fold increased risk with a more aggressive phenotype and significantly reduced survival compared to non-carriers. 1, 2

Key Germline Mutations Associated with Prostate Cancer Risk

• BRCA2 mutations have the strongest and most consistent association with prostate cancer risk (2-6 fold increase) and are found in approximately 5.3% of men with metastatic prostate cancer 1
• BRCA2 mutation carriers develop prostate cancer at earlier ages, with more aggressive phenotypes, and have significantly reduced survival times compared to non-carriers 1, 2, 3
• Other germline mutations associated with prostate cancer risk include:
  • BRCA1 (0.9% of metastatic cases), though with less consistent association than BRCA2 1, 2
  • ATM (1.6% of metastatic cases) 1
  • CHEK2 (1.9% of metastatic cases) 1
  • PALB2 (0.4% of metastatic cases) 1
  • Less commonly: RAD51D, ATR, NBN, PMS2, GEN1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, and FAM175A 1

Evidence Supporting BRCA2 as the Primary Mutation

• In patients with localized prostate cancer, germline DNA repair mutations were found in 6% of those with high-risk disease compared to only 2% in low/intermediate risk disease 1
• Studies specifically examining early-onset prostate cancer have found BRCA2 mutations in 2.3% of men diagnosed ≤55 years of age, with a 23-fold increased relative risk of developing prostate cancer by age 56 4
• The positive predictive value of biopsy using a PSA threshold of 3.0 ng/mL in BRCA2 mutation carriers is 48%—double the PPV reported in population screening studies 5
• Median survival of prostate cancer cases with germline BRCA2 mutation is significantly shorter at 4.8 years compared to 8.5 years in controls (p=0.002) 3

Clinical Characteristics of BRCA2-Associated Prostate Cancer

• All carriers of truncating BRCA2 mutations in one study developed prostate cancer at ≤65 years 6
• High PSA at diagnosis (>20 ng/mL) is significantly associated with BRCA2 mutation carrier status (6.4%, p=0.0005) 7
• Loss of heterozygosity at the BRCA2 locus is found in the majority of tumors from BRCA2 mutation carriers, suggesting that BRCA2 functions as a tumor suppressor gene in prostate cancer 3
• Multivariate analysis confirms that poorer survival in BRCA2 mutation carriers is associated with the germline mutation itself, independent of other factors 3

Screening Recommendations

• The NCCN recommends that men with germline BRCA2 mutations begin prostate cancer screening at age 40 1, 2
• Men with BRCA1 mutations should also consider beginning screening at age 40, though the association with prostate cancer is less strong 1, 2
• Targeted PSA screening based on BRCA genotype yields a high proportion of aggressive disease that requires treatment 5
• BRCA2 mutation carriers should not be managed with active surveillance as they have more aggressive disease 3

Genetic Testing Considerations

• Germline genetic testing should be considered for all patients with high-risk, very-high-risk, regional, or metastatic prostate cancer, regardless of family history 2
• Family history of breast, ovarian, pancreatic, or prostate cancer should prompt consideration of germline testing 2
• When performing germline testing, include at minimum: BRCA2, BRCA1, ATM, CHEK2, PALB2, MLH1, MSH2, MSH6, and PMS2 2

Clinical Implications

• BRCA2 germline mutation is an independent prognostic factor for survival in prostate cancer 3
• Patients with BRCA2 mutations require more aggressive monitoring and treatment approaches due to the higher likelihood of developing lethal disease 2, 3
• Identification of BRCA2 mutation carriers has implications not only for the patient but also for family members who may benefit from genetic counseling and cancer screening 2