BRCA1 AND BRCA2

BRCA1 and BRCA2 are tumor suppressor genes. This means they normally help prevent cancer by repairing damaged DNA and regulating cell growth. When either of these genes is mutated (changed), cells are more likely to grow in an uncontrolled way, which can lead to cancer.

These mutations can be inherited from a parent and are most commonly linked to breast and ovarian cancer. However, researchers have found that they are also associated with other cancer types in both men and women. BRCA-related cancers tend to occur at a younger age and may behave differently from cancers that do not have these mutations.

What types of cells normally express BRCA1 or BRCA2?

BRCA1 and BRCA2 are normally active in many types of cells throughout the body, especially those that divide and grow quickly.

BRCA1 and BRCA2 are most active in the cells of the breast and ovaries, which is why mutations in these genes are strongly linked to breast and ovarian cancer. They are also expressed in cells of the prostate, pancreas, and other tissues, which helps explain why mutations in these genes can increase the risk of cancer in those areas as well.

Inside cells, the BRCA1 and BRCA2 proteins play a crucial role in repairing damaged DNA. This repair process is especially important in tissues that experience regular cell turnover. When BRCA1 or BRCA2 is missing or not working properly, cells are less able to fix DNA damage, which can lead to the development of cancer over time.

What types of cancers are associated with BRCA mutations?

BRCA1 and BRCA2 mutations are linked to an increased risk of several types of cancer. The risk can vary depending on which gene is mutated and whether it is inherited from the mother or father.

Cancers associated with BRCA mutations include:

• Breast cancer – BRCA1 and BRCA2 mutations are best known for increasing the risk of breast cancer. People with a BRCA1 mutation have a lifetime breast cancer risk of about 55 to 72%, while those with a BRCA2 mutation have a risk of 45 to 69%. These cancers tend to occur at a younger age and are more likely to involve both breasts over time.
• Ovarian cancer – BRCA1 mutations are associated with a 30 to 60% lifetime risk of ovarian cancer, while BRCA2 mutations carry a 10 to 25% risk. This is much higher than the general population, where the lifetime risk is about 1 to 2%.
• Pancreatic cancer – People with BRCA2 mutations, and to a lesser extent, BRCA1 mutations, have a higher risk of pancreatic cancer. This applies to both men and women.
• Prostate cancer – Men with BRCA2 mutations have an increased risk of developing prostate cancer, and it often occurs at a younger age and may be more aggressive. BRCA1 mutations may also slightly increase the risk.
• Melanoma – BRCA2 mutations have been linked to a higher risk of melanoma, particularly uveal (eye) melanoma and skin melanoma. The increase in risk is smaller compared to breast and ovarian cancers.
• Stomach cancer – A modest increase in stomach cancer risk has been reported in people with BRCA2 mutations.
• Colorectal cancer – There may be a small increase in colorectal cancer risk for individuals with BRCA1 or BRCA2 mutations, though the data is less clear than for other cancer types.
• Endometrial cancer – BRCA1 mutations may slightly increase the risk of endometrial (uterine) cancer, particularly in women who have taken certain hormone therapies.
• Gallbladder and bile duct cancers – Some studies have suggested a higher risk for these cancers in people with BRCA1 or BRCA2 mutations, though this risk appears to be small.
• Liver cancer – There may be a slightly increased risk of liver cancer in individuals with BRCA2 mutations, although this is rare.

The specific cancer risks can also depend on factors like family history, age, and lifestyle. Genetic counseling and regular screening are often recommended for individuals who carry BRCA mutations.

How do doctors test for BRCA mutations?

To find out if someone has a BRCA1 or BRCA2 mutation, doctors use genetic testing. These tests look for changes in the DNA of the BRCA1 and BRCA2 genes that may increase the risk of cancer. The most common method for detecting these mutations is called next-generation sequencing (NGS). In some cases, alternative methods such as Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), or quantitative PCR (qPCR) may also be employed.

Next-generation sequencing (NGS) is a modern and highly accurate technique that can examine multiple parts of the DNA simultaneously. It can detect both small changes in a single letter of DNA (called point mutations) and large changes (such as deletions or rearrangements) in the BRCA1 and BRCA2 genes. This makes it the preferred method for BRCA testing in most laboratories.

Sanger sequencing is an older method that remains useful in some instances. It is very accurate for finding small changes in the gene, but it cannot detect larger mutations.

MLPA and qPCR are techniques that are especially helpful for identifying large changes in the DNA that other tests might miss. These methods may be used when NGS is not available or to confirm uncertain results.

Samples for BRCA testing are usually taken from blood, but saliva or cheek swabs may also be used. Testing may be done when a person has a strong family history of cancer, is diagnosed with breast or ovarian cancer at a young age, or has a personal or family history of cancers known to be associated with BRCA mutations.

Test results are typically reported as either:

• Positive – meaning a harmful mutation in BRCA1 or BRCA2 was found, which increases the risk of certain cancers.
• Negative – meaning no harmful mutations were found.
• Variant of uncertain significance (VUS) – meaning a genetic change was found, but doctors are not yet sure if it increases cancer risk.

The results of BRCA testing can help guide decisions about cancer prevention, screening, and treatment.

What is the role of BRCA immunohistochemistry in pathology reports?

In some cases, pathologists may use a test called immunohistochemistry (IHC) to look at BRCA1 or BRCA2 protein expression in a tissue sample. This test does not check for mutations in the DNA, but instead determines whether the BRCA proteins are being produced in the tumor cells.

The BRCA1 and BRCA2 proteins normally help repair damaged DNA and prevent cells from developing into cancerous cells. If a tumor shows loss of BRCA protein expression by IHC, this may suggest that the BRCA gene is not working properly. However, this loss could be due to several reasons, including a mutation, a deletion of the gene, or changes in how the gene is expressed or regulated (called epigenetic changes).

BRCA immunohistochemistry may be used in some pathology laboratories as a screening tool, especially when there is suspicion that a tumor might be related to a BRCA mutation. If the protein is absent, additional genetic testing may be recommended to confirm whether a BRCA1 or BRCA2 mutation is present.

It is important to know that BRCA IHC is not a substitute for genetic testing. Some tumors with BRCA mutations may still exhibit normal BRCA protein expression by IHC, while others with no mutation may show reduced expression. Because of this, BRCA IHC is not commonly used in routine practice, and doctors rely on genetic testing to diagnose BRCA-related cancer syndromes and to guide treatment decisions.

What is the prognosis for someone with a BRCA mutation?

The prognosis depends on many factors, including the type of cancer, stage at diagnosis, and treatment response. While people with BRCA mutations are at higher risk of developing cancer, early detection, preventive options, and targeted therapies can significantly improve outcomes.

Questions to ask your doctor

• Should I be tested for a BRCA mutation?
• What does my BRCA test result mean for me and my family?
• If I have a BRCA mutation, what are my options for reducing my cancer risk?
• How does this mutation affect my current cancer treatment plan?
• Should my relatives also consider genetic testing?