• Introduction
  The BRCA1 and BRCA2 genes are tumour suppressor genes. They play a role in DNA repair through homologous recombination, which helps maintain genome integrity and prevent the development of certain types of cancer^.
  
  However, a change or “mutation” in these genes increases the risk of prostate cancer and breast cancer in men⁴ .
  
  
• Risk of prostate cancer
  
  How BRCA germline mutations affect prostate cancer risk
  
  BRCA1/2 gene mutations are not common, but they are present in approximately 2% of prostate cancer patients. This percentage increases significantly, to approximately 12%, in men with metastatic castration-resistant prostate cancer. It is also important to note that prostate cancer linked to BRCA1/2 mutations tends to be more aggressive. There are key differences between BRCA1 and BRCA2 mutations with regard to prostate cancer:
  
  
  • Higher risk with BRCA2 mutations: a man with a BRCA2 mutation has a lifetime risk of developing prostate cancer ranging from 20 to 60%. In other words, this is 2.5 to 5 times higher than for a man without the mutation. For BRCA1 mutations, the lifetime risk is also increased, generally between 15 and 20%, which is about twice as high as for men without the mutation.
  • Earlier diagnosis with BRCA2: Men with a BRCA2 mutation are much more likely to be diagnosed with prostate cancer at a younger age, often before the age of 65. The risk of being diagnosed before the age of 65 is approximately 15%. Although BRCA1 mutations can also lead to earlier diagnosis, the link is not as strong or clear as with
  • More aggressive characteristics: Prostate cancer that develops in men with BRCA1/2 mutations often has more aggressive characteristics. This means that it is more likely to be of a higher grade (ISUP/Gleason), diagnosed at more advanced stages ( .g., spread to lymph nodes or presence of metastases at diagnosis), and may have less favourable outcomes after standard local treatments compared to men without the mutation.
    
    Indications for germline testing
    
    Detection of a mutation in the BRCA1 or BRCA2 genes can have important implications for patients and their families. It influences genetic counselling, helps guide decisions about cancer screening strategies and even treatment options. In Belgium, germline testing for BRCA1/2 is currently recommended for men with:
    
    • Prostate cancer diagnosed before the age of 55 (even if it is localised).
    • Metastatic prostate cancer (hormone-sensitive and castration-resistant).
    • A family history suggesting a BRCA mutation, such as:
      • A patient with prostate cancer and a first- or second-degree male or female relative with breast cancer (≤ 50 years of age), prostate cancer (≤ 60 years of age or metastatic), ovarian cancer or pancreatic cancer²⁶.
      • ≥ 3 cases of breast and/or prostate cancer in the family (with at least one diagnosis before age 60)²⁷ .
      • Prostate cancer and Ashkenazi Jewish ancestry.

Managing your risk: screening and monitoring

Patients with a BRCA1/2 mutation will require more extensive prostate cancer screening due to an increased risk throughout their lives. However, as BRCA2 is more strongly linked to early onset, prostate cancer screening is recommended from the age of 40, and in the case of a BRCA1 carrier, screening will begin at the age of 50. If there is a family history of prostate cancer diagnosed at a very young age, screening may begin 10 years earlier than the youngest diagnosis in the family, whichever comes first. Screening usually involves annual blood tests for prostate-specific antigen (PSA). Digital rectal examination (DRE) is less commonly offered due to its poor ability to effectively detect prostate cancer. Annual magnetic resonance imaging (MRI), with targeted biopsies if necessary, may also be offered due to its recently demonstrated effectiveness in screening a high-risk population. MRI reduces the risk of detecting insignificant prostate cancer, as well as the number of biopsies.

Impact on treatment

Currently, the impact of a BRCA1/2 germline mutation on the choice of treatment (surgery or radiotherapy) for localised prostate cancer is unknown. However, in a more advanced setting, the presence of BRCA1/2 mutations directly influences treatment decisions, as these mutations confer sensitivity to a specific class of targeted therapies: PARP inhibitors.

PARP enzymes play a key role in repairing single-strand DNA breaks. In normal cells, if PARP is inhibited, these single-strand breaks can lead to double-strand DNA breaks. However, these double-strand breaks use BRCA in particular to repair themselves. If cancer cells have a BRCA1/2 mutation, PARP inhibition leads to an accumulation of double-strand breaks that cannot be repaired. This massive DNA damage triggers cell death, a concept known as synthetic lethality.

• Breast cancer risk
  
  Men with BRCA1/2 mutations also have an increased risk of breast cancer. The estimated lifetime risk is 1% for BRCA1 and approximately 7% for BRCA2.
  
  Management and monitoring
  
  Since male mammary glands are subcutaneous, there is no indication for systemic imaging screening. Screening is based on self-palpation of a lump in the mammary glands, which are located on the pectoral muscle(^{50) .}If a lump is palpated, it is advisable to consult a doctor to determine the best course of action (ultrasound, MRI, etc.).

• Risk of transmission of BRCA predisposition Risks
  
  Just like women, male carriers can also pass on a genetic predisposition to their children. Each child, regardless of gender, has a 50% chance of inheriting the family predisposition. This means that if you have three children, none, one, two or all three may be carriers. If you are a carrier, it is therefore important to share this information with your children so that they can undergo genetic testing to determine whether or not they have inherited the family predisposition.
  
  Family planning
  
  Being a carrier of the BRCA mutation and wanting to start a family can be emotionally difficult. For people who consider the risk of transmission to be an obstacle to their family plans, one option is in vitro fertilisation (IVF), a s during which genetic testing can be performed. This allows parents to make an informed decision about continuing with the pregnancy.
  
  
•  Other genes involved in prostate cancer
  CHEK2 and ATM germline mutations
  The risk associated with CHEK2 and ATM in the development of prostate cancer is generally moderate, comparable to that associated with BRCA1. Follow-up recommendations are to begin screening at age 50, or 10 years earlier than the youngest family diagnosis, with an annual PSA blood test. The role of MRI in these germline mutations is less clear.
  
  HOXB13
  
  Among the genes involved in hereditary prostate cancer, HOXB13 (Homeobox B13) has become a major focus of research, particularly due to specific germline mutations associated with increased risk. The G84E variant has been consistently and strongly associated with an increased risk of developing prostate cancer, particularly early-onset forms (diagnosis at age 55 or younger) and familial forms of the disease. Its identification has designated HOXB13 as a gene conferring a risk comparable to BRCA2. Screening recommendations for male carriers are therefore similar to those for BRCA2 carriers.