BRCA2 Gene Mutations and Cancer Risk in Men and Women

Many people are aware that BRCA2 gene mutations are associated with an increased risk of breast cancer, but these mutations have also been linked with ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, and leukemia.

While BRCA2 mutations are often linked together with BRCA1 mutations, there are many important differences. The two mutations confer different risks for breast and ovarian cancer and are also associated with different cancers in other regions of the body, including pancreatic cancer.

Understanding the differences in these mutations is important in understanding your family history as well. Your healthcare provider may be more concerned if you have one close relative who had breast cancer and one who had pancreatic cancer than if you had two with breast cancer. Pancreatic cancer is less common than breast cancer, and when it occurs in association with breast cancer it raises a flag suggesting either a BRCA1 or a BRCA2 mutation may be present.

Let's look at how exactly a BRCA2 mutation can increase cancer risk, the cancers associated with this mutation, who should be tested, and the options available to reduce cancer risk or at least detect these cancers as early as possible.

Definition

A quick review of genetics can make BRCA mutations easier to understand. Our DNA is made up of 46 chromosomes, 23 from our fathers and 23 from our mothers. Genes are sections of DNA found in chromosomes that code for specific functions. They are like a blueprint the body uses to make proteins. These proteins then have a wide array of functions ranging from the hemoglobin in your blood that binds oxygen, to protect you from cancer.

Mutations are areas of damaged genes. When the gene or blueprint is damaged, an abnormal protein can be made which doesn't work like that normal protein. There are many different types of BRCA mutations. The "code" in genes is comprised of a series of letters (known as bases). Series of these letters tell your body to put different amino acids in order to make a protein. Not uncommonly a base is deleted (deletion mutations), sometimes one is added, and sometimes several of the bases are rearranged.

How Cancer Is Caused

The BRCA gene is a specific gene called a tumor suppressor gene which has the blueprint for proteins which help to protect us against developing cancer.

Damage (mutations and other genetic changes) occurs in the DNA of our cells every day. Most of the time, proteins (such as those coded for in BRCA tumor suppressor genes) repair the damage or eliminate the abnormal cell before it can go through the process of becoming cancer.

Prevalence

Having a BRCA mutation is relatively uncommon. BRCA1 mutations are found in roughly 0.2% of the population, or 1 in 500 people.

BRCA1 mutations are more common in those of Ashkenazi Jewish heritage, whereas BRCA2 mutations are more variable.

Who Should Be Tested?

At the current time, it's not recommended that BRCA2 testing be performed for the general population. Instead, those who have a personal or family history of cancer may wish to consider testing if the pattern and types of cancer found suggest that the mutation may be present. People who may wish to consider BRCA testing include:

• People who have been diagnosed with breast cancer at a young age (for example, less than age 50) or triple-negative breast cancer diagnosed before age 60
• People who have been diagnosed with ovarian cancer
• People who have been diagnosed with breast cancer at any age, but have relatives who have had breast cancer at a young age, ovarian cancer, or pancreatic cancer
• People who have a relative who has had male breast cancer
• People who have a relative who has had ovarian cancer
• People who have two or more relatives who have had breast cancer at a young age
• People of Ashkenazi Jewish heritage who have had breast, ovarian, or pancreatic cancer at any age
• People who have a relative who has been diagnosed with a BRCA mutation

It's important to note that there are a number of non-BRCA gene mutations that raise breast cancer risk (BRCA mutations are responsible for only 9% to 29% of hereditary breast cancers), and testing for many of these mutations may wish to be considered as well.

Cancers Caused By Mutation

Having a BRCA2 mutation is different than BRCA1 mutations (which was what Angelina Jolie had and is spoken of often) and raises the risk of several different types of cancer. At the current time, however, our knowledge is still growing and this may change in time. Cancers which are more common in people with BRCA2 mutations include:

• Breast cancer: Breast cancer due to a BRCA mutation accounts for 20% to 25% of hereditary breast cancers. Women who have a BRCA2 mutation have a 45% chance of developing breast cancer by the age of 70 (slightly lower than with a BRCA1 mutation). Men with a BRCA1 mutation also have a 1% risk of breast cancer, and a 6% risk with a BRCA2 mutation. Women and men with a BRCA mutation also tend to develop breast cancer at a younger age.
• Ovarian cancer: Women who have a BRCA2 mutation have an 11% to 17% chance of developing ovarian cancer by the age of 70 (also somewhat lower than with a BRCA1 mutation). Women with a BRCA2 mutation tend to develop ovarian cancer at a younger age than women without the mutation.
• Prostate cancer: Men with both BRCA1 and BRCA2 mutations are 4.5 to 8.3 times more likely to develop prostate cancer. Those with BRCA2 mutations (unlike BRCA1) often develop aggressive prostate cancer and the 5-year survival rate is around 50%(compared to a 99% 5-year survival rate in the general population).
• Pancreatic cancer: The risk of pancreatic cancer is also increased. For those who develop pancreatic cancer, one review noted that while survival for those with BRCA2 mutations was lower than those who developed sporadic pancreatic cancer, those with the mutations did much better with chemotherapy than non-mutation carriers.
• Leukemia: People with BRCA1 mutations do not appear to have an increased risk of leukemia. The risk does appear to be elevated in women with BRCA2 mutations who have had chemotherapy for breast cancer.

People who inherit two copies of a mutated BRCA2 gene, in addition to the cancers above, are more likely to develop solid tumors in childhood and acute myeloid leukemia.

Screening guidelines recommend that all people have a screening colonoscopy (or comparable testing) at the age of 50.

Lowering Risk of Death

There are two different management approaches for people with BRCA2 mutations, both of which are designed to reduce the chance that a person will die from one of the cancers of risk:

• Early detection: Early detection is the process of trying to find a cancer which has formed at the earliest stage possible. With many cancers, we know that survival is higher when it's found at an early stage (for example, stage 1 or stage 2) than if it is discovered at a later stage (such as stage 4). With early detection, the goal is to find cancer before it would otherwise cause the symptoms that would lead to its discovery. We don't have methods to detect all cancers at these early stages, and the tests we do have are not perfect. For example, despite having had a normal mammogram, some women are diagnosed with breast cancer shortly thereafter.
• Risk reduction: Risk reduction strategies work to reduce the risk that a cancer will develop in the first place. They are designed to prevent cancer from occurring. Methods of reduction may include surgery or medications (chemoprevention).

Most approaches to a genetic predisposition to cancer include either screening or risk reduction, but there is one test that can do both. Colonoscopy can be used to detect colon cancer in the earliest stages. It can also be used to reduce the risk of a person getting cancer if a pre-cancerous polyp is found and removed before it becomes malignant.

Screening and Treatment

We don't have screening or treatment options for all cancers linked with BRCA2 mutations. It is also early in the process of determining which screening methods and treatments are best, so it's important to have a healthcare provider who is experienced in caring for BRCA mutation carriers. Let's look at options by cancer type.

Breast Cancer

• Screening for women: Depending on your mutation and family history, screening is usually started at an age much younger than for people without a mutation. Screening tests may include mammography, breast MRI, and ultrasound. Mammograms are less accurate in younger women due to the density of their breasts and MRIs are usually done in addition to a mammogram.
• Screening for men: Since breast cancer is rare in men, and BRCA mutations are associated with fewer cases of breast cancer, routine screening is not recommended. For men who have had breast cancer, 2020 guidelines from the American Society of Clinical Oncology state that they should be offered yearly mammography on the unaffected breast as a screening tool (not breast MRI as with women).
• Chemoprevention: The medications known as selective estrogen receptor modulators (SERMS) can reduce the risk of developing breast cancer up to 50%. Medications available include tamoxifen and Evista (raloxifen).
• Surgery: A bilateral mastectomy greatly reduces the risk of developing breast cancer. Timing of surgery, however, depends on many factors, including a woman's reproductive plans and desire to breastfeed.

Ovarian Cancer

• Screening: We don't currently have a satisfactory screening method for ovarian cancer. Healthcare providers may consider tests such as transvaginal ultrasound, clinical exams, and CA-125, but we do not yet know if such screening improves survival.
• Chemoprevention: The use of birth control pills may reduce the risk of ovarian cancer up to 50% with longer-term use.
• Surgery: Removal of the ovaries and fallopian tubes (salpingo-oophorectomy) can reduce the risk of ovarian cancer. As with breast cancer after a mastectomy, some women may still get ovarian cancer but it is much less common.

Prostate Cancer

• Current screening for prostate cancer is riddled with controversy, including that surrounding PSA testing. For those who carry a BRCA2 mutation, it's important to work with a urologist who is familiar with the more aggressive disease found in men with these mutations. Current guidelines for the general population should not be followed for men who have BRCA2 mutations. The American Cancer Society suggests a yearly PSA and digital exam beginning at the age of 40 for men who have a higher risk.

Pancreatic Cancer

• We don't have clear guidelines on screening for pancreatic cancer, though studies suggest that in appropriate patients (those over the age of 50 and perhaps 60), screening may be beneficial.

A Word From Verywell

People who carry a BRCA mutation have an increased risk of developing several types of cancer, but having one of these mutations does not mean you will get cancer. Currently, genetic testing for the BRCA gene is only recommended for those who have a personal or family history that suggest the mutation may be present.