Why is the BRCA (Breast Cancer) gene a risk factor for ovarian and breast cancer as opposed to ovarian and testicular cancer?

From the Guidelines

The BRCA gene mutations are risk factors for ovarian and prostate cancer rather than ovarian and testicular cancer due to their specific biological mechanisms, with BRCA1 and BRCA2 genes normally functioning as tumor suppressors by helping repair damaged DNA, preventing genetic alterations that can lead to cancer. When these genes are mutated, they cannot properly repair DNA damage, allowing cells to accumulate genetic errors that may lead to cancer development. While BRCA mutations significantly increase the risk of ovarian cancer in women (up to 40-60% lifetime risk with BRCA1 mutations), they specifically affect the prostate rather than the testes in men. This is because BRCA mutations primarily impact tissues that are hormone-responsive and have high cell turnover rates. The prostate gland, which is highly influenced by androgens and undergoes more cellular changes throughout life, is more susceptible to the DNA repair defects caused by BRCA mutations than testicular tissue. Men with BRCA2 mutations have approximately 2-6 times higher risk of developing prostate cancer compared to the general population, and these cancers often occur at younger ages and may be more aggressive, as supported by studies such as 1 and 1. Testicular cancer, by contrast, has not shown a strong association with BRCA mutations in research studies, suggesting different genetic and environmental factors contribute to its development. Key points to consider include:

• BRCA1 and BRCA2 mutations are inherited in an autosomal dominant fashion, but act recessively on the cellular level as tumor suppressor genes involved in double-stranded DNA (dsDNA) break repair, as noted in 1.
• Female carriers of mutations in BRCA1 or BRCA2 have a lifetime risk of breast cancer of 50%–85%, and an increased risk of ovarian cancer, with an estimated lifetime risk of 10–40% for BRCA1 carriers and 10%–20% for BRCA2 carriers, as reported in 1.
• Men with BRCA2 mutations have an increased risk of prostate cancer, with approximately 5%–10% lifetime risk, as mentioned in 1 and further supported by 1 and 1. Given the most recent and highest quality evidence from 1, it is clear that BRCA gene mutations pose a significant risk for ovarian and prostate cancer, and individuals with these mutations should be closely monitored and managed to reduce their risk of developing these cancers.

From the Research

BRCA Gene and Cancer Risk

• The BRCA gene is a risk factor for ovarian and prostate cancer due to its role in maintaining genome integrity and DNA repair [(2,3,4)].
• BRCA1 and BRCA2 are tumor suppressor genes, and mutations in these genes can lead to a increased risk of breast, ovarian, and prostate cancer [(2,3,4)].
• The risk of ovarian cancer is higher in individuals with BRCA1 mutations (30-40%) compared to those with BRCA2 mutations (10-15%) 2.

Prostate Cancer Risk

• BRCA2 mutations are associated with a greater risk of prostate cancer (OR = 2.64) compared to BRCA1 mutations (OR = 1.35) 5.
• The frequency of BRCA2 mutations is higher than BRCA1 mutations among patients with prostate cancer 5.
• BRCA2 mutations are associated with higher prostate cancer mortality, whereas BRCA1 mutations are not 5.

Ovarian Cancer Risk

• BRCA1 and BRCA2 mutations account for approximately 10-12% of ovarian cancers 6.
• Patients with BRCA1/2 mutations have improved chemosensitivity to platinum agents, longer disease-free intervals, and longer survivals compared to non-hereditary counterparts 6.
• Tumors arising in BRCA1/2 mutation carriers are sensitive to PARP inhibitors, which may be a potential therapeutic strategy for ovarian cancer 6.