• Breast cancer affects 1 in 8 women in the United States. Hereditary breast cancer accounts for approximately 5-10% of these breast cancers. Most cases of breast cancer are sporadic.
• Ovarian cancer affects about 1 in 100 women. Hereditary ovarian cancer accounts for 10-15% of these cases. Most cases of ovarian cancer are sporadic.
• 80-90% of women with hereditary breast and ovarian cancer can be linked to mutations in the BRCA genes.
• Individuals of Ashkenazi Jewish descent have a significant risk to have a mutation in the BRCA gene and are therefore at a higher risk to develop breast and/or ovarian cancer.
What Is the BRCA Gene?
We have about 25,000 genes in every cell of our body. These genes are packaged into long strands of DNA called chromosomes. To visualize this, imagine that a chromosome is a string of pearls and each individual pearl is a gene. We all have 23 pairs of chromosomes in each cell and for each pair, one chromosome is inherited from our mother and the other is from our father. The genes located on the chromosomes, therefore also come in pairs.
Each gene in our body has a unique function, or job. Sometimes our genes are not structured properly. When a gene does not look like it should, it will not work properly and cannot do its job. We call a change in the genes a mutation.
BRCA 1 and BRCA 2 are examples of two genes. They both have the same “job” -- to stop our bodies from allowing cancer to grow. BRCA1 and 2 are tumor suppressor genes and are very important genes. Therefore, if someone has a mutation in either BRCA gene, they are at a higher-than-average risk to develop cancer. If a woman develops breast or ovarian cancer because she has a mutation in her BRCA 1 or 2 gene, the name of her condition is Hereditary Breast and Ovarian Cancer (HBOC). Individuals with a mutation are commonly referred to as “BRCA carriers.”
In the general population the incidence of BRCA1 mutation is between 1 in 500 and 1 in 800. The incidence of BRCA2 mutation is even lower. Individuals of Ashkenazi Jewish descent, however, have a 1 in 40, or 2.5%, risk of having a mutation. In other words, Ashkenazi Jews have a higher-than-average risk to be BRCA carriers. The chance to be a BRCA carrier is 1 in 10 for an Ashkenazi Jewish woman who has already had breast cancer.
The Jews of Eastern Europe (“Ashkenazi Jews”) have lived in small insular communities for hundreds of years. Mutations in genes were present in these communities, but were not common. The communities changed over time; there was migration outside, isolation, and a decrease in size. As a result, the mutations that had been rare earlier now became more prevalent, and a higher percentage of the population became carriers. This phenomenon is known as the “founder effect.” There are 3 common BRCA mutations in the Ashkenazi Jewish population due to the founder effect.
We are not the only population to have high carrier frequencies for this reason. For example, sickle cell disease tends to affect African-Americans, beta thalassemia affects Mediterranean populations, and Tay-Sachs disease is also common among the French Canadian, Irish, and Louisiana Cajun populations.
How one identifies with their religion does not define their ancestry. An individual does not need to practice Judaism to be considered Jewish. If an individual has at least one grandparent who descended from an Ashkenazi Jew, that person is at risk of being a carrier for a Jewish genetic disease.
Risks Associated with Being a BRCA Carrier
When someone is found to be a BRCA carrier, there are 2 major implications to consider: his or her own health and the health of her family.
1) Increased Risk for Cancer
If a woman has a BRCA mutation, she has about a 55-85% risk to develop breast cancer (vs. the general population risk of about 12%). There is also an increased risk to develop as second cancer in the opposite breast. The risk to develop ovarian cancer is about 20-65% (vs. the general risk of about 1.5%).
In addition to these cancers, BRCA carriers (both females and males) are also at increased risk to develop colon cancer, pancreatic cancer, melanoma, and male breast and prostate cancers.
We would expect BRCA carriers to develop cancer at a relatively young age since they are born with one non-working BRCA. Remember that BRCA carriers are increased risk to develop cancer, but there is no guarantee that a carrier will ever get cancer.
2) Risk of Transmitting Mutation to Offspring
BRCA carriers have one working copy of their BRCA gene and one non-working copy. Each time they have a child, there is a 50% chance they will transmit the working BRCA and a 50% chance they will transmit the one with the mutation. Each child of a BRCA carrier, therefore, has a 50% risk of inheriting the mutation. Another way to see it is that if someone is a carrier, each of his or her siblings has a 50% chance of being a carrier since at least one of their parents is a BRCA carrier.
This pattern of inheritance is called autosomal dominant.
How to Get Tested
BRCA testing involves a simple blood draw. The blood is sent to a lab that looks for mutations in both BRCA 1 and BRCA 2. For individuals of Ashkenazi Jewish descent, there is a test that looks for three common founder mutations only. About 95% of Ashkenazi BRCA carriers will have one of these three mutations. If someone is suspected to be a BRCA carrier and he or she does not have one of these common mutations, the genetic counselor may order a more comprehensive genetic test to look for different mutations.
BRCA testing can be done either through one’s OB/GYN or through a genetics clinic. Some women may feel more comfortable with their regular OB/GYN and are encouraged to continue with them if they desire. Many OB/GYNs have relationships with genetics clinics and will refer their high-risk patients for genetic counseling.
If one chooses to go to a genetics office, he or she will meet with a genetic counselor and/or medical geneticist. The counselor will take a complete family history and will assess the individual’s needs for genetic testing. The counselor may recommend certain tests and will discuss options for the future. Genetic counselors have up-to-date knowledge of testing recommendations.
The results will be ready about 2 weeks later, and the counselor will review them with the patient. If the patient is found to be a carrier, the counselor will discuss risk-reducing options with the patient and will encourage him or her to tell family members.
Genetics offices are often located at academic medical centers. Most genetic counselors are allotted enough time to have detailed discussions about their patients’ family and medical histories and to describe the genetic testing process. Genetic counselors are trained to attend to the genetic and psychosocial needs of the patient.
The cost of getting tested depends on one’s health insurance. Some insurance companies will cover the entire cost of the genetic testing and genetic counseling in full, while others might partially cover it or not cover it at all. This will be discussed at the time your appointment is made.
To make an appointment for your genetic counseling with us at the Division of Reproductive Genetics at Montefiore Medical Center, call us at (718) 405-8150.
Benefits of Testing
1) A positive test result will empower you with the information to take steps towards reducing your risk to develop cancer (see “Preventative Measures for BRCA Carriers” below). If you are affected with cancer, your physician will use this information to make decisions about your treatment plan.
2) A negative result rules out the most common cause of hereditary breast and ovarian cancer.
3) Your results have an impact on the rest of your family; they will help other family members identify their risks for hereditary cancer.
Limitations of Testing
1) BRCA mutations only account for about 80-90% of hereditary breast and ovarian cancer. Therefore, a negative result does not necessarily mean that the cancer in your family is spontaneous-it still could be hereditary, but due to a mutation in a non-BRCA gene.
2) A negative result does not mean that you and your relatives have no risk for developing cancer.
3) A positive result does not guarantee that you will develop cancer, only that you have a significantly increased risk.
4) About 1% of individuals who get BRCA testing will receive a result called a variant of uncertain significance. This means that there is a genetic change in the BRCA gene, but it is not known if this change is associated with HBOC. It may be a benign change, but it may also be dangerous. More research is needed to determine the effects, if any, on cancer development.
Preventative Measures for BRCA Carriers
Once a woman has been identified as being a BRCA carrier, there are measures she can take to reduce her risk of developing cancer or to detect cancer at an earlier, more treatable stage:
1) Increased surveillance: It is recommended that female BRCA carriers be vigilant in their screening for breast cancer. Frequent monitoring for breast cancer includes: monthly breast self-examinations starting at age 18, annual or semi-annual clinical breast exams starting at age 25, annual mammography starting at age 25, and breast MRI or ultrasound (depending on doctor’s recommendations). Monitoring for ovarian cancer includes: annual or semi-annual transvaginal ultrasound, annual or semi-annual CA-125 blood test, and annual pelvic exams. Clinical decisions concerning surveillance may differ from woman to woman and consultation with a physician is encouraged.
2) Prophylactic surgery: A woman who is a carrier will be counseled that she may decide to have both of her breasts removed (mastectomy). This reduces her risk to develop breast cancer by up to 95%. Another risk-reducing surgery is removal of the ovaries (bilateral salpingo-oophorectomy). This outpatient procedure would reduce her risk to develop ovarian cancer by 97-98% and for breast cancer by about 50%. If a woman opts to have her ovaries removed, she will essentially be putting herself into menopause. For this reason, oophorectomy is recommended only once a woman is done child-bearing. The decision to have a mastectomy and/or oophorectomy is very personal one. A woman may decide to make this decision with the help of her physician, family, and spiritual leader.
3) Preventative drug therapies: Research has shown that certain medications have been implicated in reducing the incidence of breast and ovarian cancer in BRCA carriers. Tamoxifen, for example, has been proven to reduce the risk of breast cancer for women with BRCA mutations by more than half. In addition, oral contraceptive pills can reduce the risk of ovarian cancer in women with BRCA mutations by up to 60%.
Males Can Be BRCA Carriers Too!
While women BRCA carriers have a heightened risk for breast and ovarian cancers, there are also potential implications for male carriers. Male BRCA carriers have up to a 10% risk of developing breast cancer and have an increased risk for developing pancreatic and prostate cancer. Annual checkup with a primary care physician is recommended for male carriers.
Most males who are BRCA carriers will not develop cancer, but they still have the same 50% risk as a female carrier to transmit the mutation to their offspring. A male whose parent is a known carrier is encouraged to consider BRCA testing so that his children will know if they are at risk of being carriers as well.
The Importance of Family History
When you go for your genetics consultation, the genetic counselor will take a detailed family history. The family history, or pedigree, is an important tool for the genetic counselor to assess whether BRCA testing is appropriate. Hereditary breast and ovarian cancer is suspected if there are multiple cases of breast cancer, especially if they are at an early age. Additional ‘clues’ are: relatives with ovarian cancer, breast and ovarian cancer in the same individual, women with bilateral breast cancer, and male breast cancer.
Before meeting with the genetic counselor, you are encouraged to take the time to inquire about your family. The more information you have, the better the genetics professional can assess your risk.
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