Breast cancer is one of the most common forms of cancer affecting women worldwide. While most cases of breast cancer are sporadic, which means they occur by chance, some patients have a hereditary form of this disease. Hereditary breast cancer accounts for about 5-10% of all breast cancer cases and is caused by inherited genetic mutations that increase an individual's risk for developing the disease. Hereditary breast cancer is primarily associated with mutations in specific genes that play key roles in repairing genetic material (DNA) and regulating cell growth. The most well-known genes associated with hereditary breast cancer are BRCA1 and BRCA2, but other genes such as TP53, PTEN and PALB2 also contribute to risk.
BRCA1 and BRCA2 genes
BRCA1 (Breast Cancer 1) and BRCA2 (Breast Cancer 2) genes are among the most important genes associated with an increased risk of breast and ovarian cancer. Their mutations significantly increase the risk of developing these and other types of cancer. These genes code for proteins that are crucial for DNA repair. They play an important role in the process of the so-called homologous recombination repair of DNA double breaks, which is critical for maintaining genomic stability. When these proteins are functional, they help prevent cancer development by maintaining the integrity of genetic material.
The protein encoded by the BRCA1 gene participates in various cellular processes including DNA repair, cell cycle control, regulation of transcription, and maintenance of genomic stability. BRCA1 acts as part of a larger complex of proteins that recognize DNA damage and initiate repair. The protein encoded by the BRCA2 gene specifically assists in the process of homologous recombination repair by ensuring proper binding and stabilization of DNA during double-strand break repair. BRCA2 helps ensure accurate and efficient DNA repair, thereby preventing the accumulation of genetic damage. Mutations in the BRCA1 and BRCA2 genes lead to reduced functionality or complete loss of function of the proteins they create (encode). This results in the inability of cells to effectively repair DNA damage, which can lead to the accumulation of genetic changes and, eventually, the development of cancer.
Women with a BRCA1 gene mutation have a 55-65% chance of developing breast cancer by the age of 70, while the risk of developing ovarian cancer is 39-46%. BRCA1 mutations are also associated with an increased risk of other cancers, including fallopian tube, peritoneal, prostate (in men), and increased risk of colon and pancreatic cancer. Women with a BRCA2 gene mutation have about a 45% risk of developing breast cancer by the age of 70, while the risk of developing ovarian cancer is 11-17%. BRCA2 mutations are associated with increased risk of pancreatic cancer, prostate cancer (in men), stomach cancer, melanoma and other types of cancer.
Other high-risk genes
Mutations in the TP53 gene cause Li-Fraumeni syndrome, which significantly increases the risk of developing various types of cancer, including breast cancer. TP53 encodes the p53 protein, a key regulator of the cell cycle and apoptosis.
Mutations in PTEN are associated with Cowden syndrome, characterized by multiple
non-cancerous growths and an increased risk of breast, thyroid and endometrial cancer. PTEN is a tumor suppressor gene involved in the regulation of the cell cycle and apoptosis.
PALB2 works with BRCA2 to repair DNA. Mutations in PALB2 increase the risk of breast cancer, although the risk is lower than for BRCA1/2 mutations.
Moderate and low risk genes
There are also genes that moderately or slightly increase the risk of breast cancer. These include CHEK2, ATM and RAD51C/D. Mutations in these genes do not carry as high a risk as BRCA1/2 mutations, but they still play a role in hereditary breast cancer.
Risk factors for hereditary breast cancer
It is not always easy to assess whether the occurrence of breast cancer in female patients is related to heredity or not. In general, we can say that in most cases the hereditary component is not crucial, but some factors can help us in further treatment and assessment of possible heredity.
Positive family history: A strong family history of breast cancer is one of the most significant indicators of hereditary breast cancer. People with multiple first-degree relatives (mother, sister, daughter) who have been diagnosed with breast cancer, especially at a young age, have a higher risk.
Inherited syndromes and mutations: As mentioned, inherited mutations in genes such as BRCA1, BRCA2, TP53, PTEN and PALB2 significantly increase the risk of breast cancer. Genetic testing can identify these mutations and help assess an individual's risk.
Positive personal history: People diagnosed with breast cancer at a young age or who have had multiple cancers are more likely to carry genetic mutations associated with hereditary breast cancer.
Ethnicity: Certain ethnic groups have a higher prevalence of specific genetic mutations. For example, Ashkenazi Jewish women have a higher frequency of BRCA1 and BRCA2 mutations.
Diagnostics and genetic testing
Genetic counseling is a crucial step for people considering genetic testing. A genetic counselor can assess personal and family medical history, discuss the potential benefits and limitations of genetic testing, and provide support throughout the testing process. Genetic testing involves analyzing DNA, usually from a sample of blood or saliva, to identify mutations in specific genes associated with an increased risk of breast cancer. Testing can be targeted (focused on specific genes suspected to be mutated in the family) or more extensive (analysis of multiple genes simultaneously). Test results can be positive (mutation found), negative (no mutation found)
or a variant of unknown significance, meaning that a mutation has been found but its effect on cancer risk is not clear. Positive results can guide decisions about risk-reduction strategies, while negative results can provide reassurance but do not eliminate cancer risk entirely.
Risk management and prevention
For people with a high genetic risk of breast cancer, there are several strategies to manage and reduce the risk. Increased surveillance can lead to earlier detection and improved outcomes. This usually includes:
- Breast self-examination: Regular self-examinations to detect any changes or lumps
- Clinical breast examination: Regular doctor's examinations
- Mammography: Annual mammograms starting at a younger age than in the general population
- Magnetic Resonance (MR): Breast MRI is often recommended along with mammography for high-risk women, as it is more sensitive in detecting cancer in dense breast tissue.
Prophylactic (preventive) surgery can be considered for people with a high risk of the disease. Prophylactic Mastectomy refers to the removal of healthy breasts, thereby reducing (but not completely eliminating!) the risk of breast cancer by about 90%. Prophylactic oophorectomy refers to the removal of the ovaries to reduce the risk of ovarian cancer, which is also increased in BRCA1/2 mutation carriers, and may further reduce the risk of breast cancer by reducing the levels of estrogen produced in the ovaries.
Furthermore, drugs such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors can reduce the risk of developing breast cancer in high-risk women. Tamoxifen and raloxifene are examples of SERMs, while anastrozole and letrozole are aromatase inhibitors used in postmenopausal women. These drugs must be taken under the control of an oncologist.
Adopting a healthy lifestyle can also help reduce the risk of breast cancer. A diet rich in fruits, vegetables and whole grains and low in processed foods and red meat can help reduce the risk of cancer. Regular physical activity helps maintain a healthy weight and reduces the risk of breast cancer, as does avoiding alcohol and smoking.
In conclusion, in case hereditary breast cancer is suspected, it is always a good idea to consult your doctor. In the event that the oncologist confirms a justified suspicion of heredity, the patient will be referred for genetic testing. A positive result can bring a certain psychological stress for the carrier, but it also enables the application of preventive techniques and early detection methods both for the tested person and for possibly affected other family members.
For more information on genetic testing and to schedule a test, please contact our team.
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