What is it?

A DNA test that includes the analysis of one or multiple mutations in the BRCA1 and BRCA2 genes using a multi-step process:

  • Mutation-specific: To screen at-risk family members for a known mutation previously identified in the index patient diagnosed with breast/ovarian cancer.
  • Population-specific: To screen for a limited number of mutations occurring at an increased frequency in certain ethnic groups (e.g. Ashkenazi Jews, Afrikaners of European descent).
  • Full gene screen: To identify the cancer-causing mutation in affected or high-risk patients who tested negative during the initial screen for family/population-specific mutations.

It is important to remember that despite the increased risk, not every person with an inherited BRCA1 or BRCA2 abnormality develops cancer. First-degree relatives of affected patients have a 50% chance of inheriting the faulty gene. Women without an inherited breast cancer gene abnormality have on average an approximately 10% risk of developing breast cancer over a 90-year life span, and 1.8% risk of ovarian cancer. In men with a BRCA mutation the lifetime risk is approximately 6%, which is 80 times greater than in men without the familial risk.
The risks associated with BRCA1 and -2 mutations are affected by:

  • The effect of the specific BRCA1/2 mutation on the protein’s ability to suppress cancer
  • How well other genes work in combination with BRCA1/2 to protect against cancer
  • How certain genes react in the presence of environmental exposures such as lifestyle changes or medication

BRCA1/2 mutation screening is typically performed using a blood sample. However, when the person considered for genetic testing has had a bone marrow transplant using bone marrow donated from another person, the testing should be done on a blood sample stored before the transplant or from a biopsy or tissue scraping.

When do I recommend it?

A family history suggesting an inherited pattern and early onset breast cancer are the most important criteria used when BRCA1 and BRCA2 mutation screening is considered. The following can be used as general guidelines for genetic testing, preferably following pre-test counseling by a registered genetic counselor to explain both the benefits and limitations of the test:

  • Familial risk: 4 close relatives diagnosed younger than 60 years;  3 close relatives diagnosed younger than 50 years;  2 close relatives diagnosed younger than 60 years and ovarian cancer in the family; male breast cancer and any family history of breast cancer
  • Ethnic risk: Founder populations such as patients of Ashkenazi Jewish or Afrikaner ancestry with a family history of breast cancer
  • Personal risk: Bilateral breast cancer at a relatively young age; ovarian cancer diagnosed younger than 30 years

Women who are very anxious about their breast cancer risk or family history could benefit from a genetic counseling consultation, where these anxieties can be addressed and an individual risk assessment can be done.

The importance of genetic counseling in the context of BRCA testing cannot be overemphasized. The implications of a potential positive/negative test result needs to be carefully considered in relation to treatment options and the impact on other family members. During the counseling session the patient or his/her close relatives are given the opportunity to decide for or against testing, based on the particular situation and a process of risk assessment following the construction of a detailed family pedigree. Genetic counseling by a healthcare practitioner trained in this specialized field will therefore not always result in genetic testing. Post-test genetic counseling should also be encouraged by clinicians.

Testing is discouraged in children under the age of 18 years, because no safe methods currently exist to help prevent breast cancer in young girls. Furthermore, everybody should be given the opportunity to decide for themselves whether they want information about their lifetime cancer risks.

What are its benefits?

Genetic testing in a familial context is most beneficial when it starts with a family member diagnosed with early-onset breast or ovarian cancer. Once the cancer-causing mutation has been identified in the index case, at-risk family members could then be screened reliably for the same mutation to exclude or confirm its presence.

Even though a positive BRCA1/2 test result does not mean that the person will definitely get breast cancer, many women with an abnormal gene assume they will.  Detection of a BRCA1/2 mutation may trigger anxiety, anger or depression. To prevent such responses and to benefit from genetic testing, pre- and post-test genetic counseling is strongly recommended.

An abnormal test result in a healthy individual justifies intensified screening intervals to detect any signs of cancer development at an early stage, when the cancer is most treatable and curable. Some women may consider prophylactic surgery before cancer cells have an opportunity to form, but although the risk is significantly reduced it is not entirely eliminated. Testing may also be beneficial in patients already diagnosed with cancer, since detection of a BRCA mutation would improve the accuracy of risk assessment on which to base future treatment decisions and surveillance intervals.

Finally, knowledge about a genetic abnormality may influence treatment decisions (e.g. tamoxifen) and implementation of lifestyle changes. In a landmark study performed by King et al. (2003) in Ashkenazi Jewish women, it was shown that a healthy lifestyle could protect against development of cancer in BRCA1 and BRCA2 mutation carriers. Approximately 50% of breast cancer patients did not have a family history of breast/ovarian cancer and the onset of breast cancer was significantly delayed in the absence of obesity and with high physical activity.

A normal test result without knowledge of the family-specific causative mutation could be confusing as it could either mean (1) that the person has a normal gene because she/he did not inherit the genetic abnormality or (2) that the result is uninformative because the family has a genetic abnormality that cannot yet be identified. Even if the causative mutation has been excluded in an at-risk family member, routine screening for breast cancer is still important.

Contrary to previous belief that exclusion of a causative BRCA1 or BRCA2 mutation reduces the risk to that of the general population (from ~85-10%), recent studies have shown that close relatives without the cancer-causing BRCA mutation have a greater chance (3-fold increased risk by age 50 years) to develop cancer compared with the general population. These findings highlight the role of modifier genes (e.g. those involved in oestrogen or folate metabolism) and shared environmental risk factors (e.g. obesity, inactivity), in masking or exacerbating the effect of single genes. It may also provide a scientific basis for application of non-diagnostic DNA tests in the context of breast cancer, with the aim to exclude potential gene-environment mismatches relating to the emerging sciences of pharmacogenetics and nutrigenetics. The combined effect of genetic and lifestyle risk factors determine breast cancer pathology, which is interconnected with response to medical and nutrition intervention.

Scientific rationale

The potential for accurate risk assessment is the key motivator for undergoing BRCA1/2 mutation screening. Several studies have shown that uncertainty regarding breast cancer risk is a major cause of stress and reduced quality of life.

Different risk implications have been reported for BRCA1 and BRCA2:

Cancer risk associated with BRCA1: Female mutation carriers have a 44-78% risk of breast cancer and an 18-54% risk of ovarian cancer by age 70.
Cancer risk associated with BRCA2: Female mutation carriers have a 31-56% risk of breast cancer and a 2.4-19% risk of ovarian cancer by age 70.

In families with multiple affected members the upper end of these risk estimates is likely to be appropriate due to co-inheritance of possible modifier genes and shared environmental exposure.

BRCA1 and -2 mutation carriers have a significantly increased risk of bilateral breast cancer and are also at increased risk of pancreatic, prostate, endometrial, and cervical cancer. BRCA2 mutation carriers also seem to have an increased risk of gall bladder/bile duct cancer and malignant melanoma. Male mutation carriers have a 6% risk of breast cancer by age 70, with a cumulative risk of nearly 20% for prostate cancer by age 80 years.

DNA sequencing of the entire coding regions of the BRCA1 and BRCA2 genes is the ultimate method for the detection of deleterious mutations in these complex genes. However, to improve cost-effectiveness, a diagnostic pre-screen focusing on detection of recurrent or founder mutations is routinely used in genetically homogeneous populations prior to more extensive analysis in mutation-negative patients. Founder mutations have been described in various populations, including the Ashkenazi Jews and white Afrikaner population of South Africa. 

Approximately 1 in 40 Ashkenazi Jews – with our without breast cancer – has a defect in the BRCA1 or BRCA2 gene. In a study published in the New England Journal of Medicine in 1997, 2,3% of the more than 5300 men and women tested had one of the three genetic abnormalities known to be associated with a high risk of breast cancer in the Jewish Ashkenazi population. In a more recent study published in 2007 in the Journal of the American Medical Association on data obtained in 3000 women from different ethnic groups, analysis of the BRCA1 gene revealed abnormalities in the following proportion of breast cancer patients:

  • 8.3% of Ashkenazi Jewish women
  • 3.5% of Hispatic women
  • 16.7% of Africa American women younger than 35 years
  • 2.2% of white women who were not Ashkenazi Jews

BRCA1 and BRCA2 mutations are the underlying cause of breast cancer in approximately 52% and 32%, respectively, in families with multiple affected individuals. In patients without a strong family history of cancer, mutations in these genes cause only 10% to 20% of breast cancer.  The risk conferred by BRCA1/2 mutations is furthermore modified by other genetic and environmental factors, and a large proportion of patients with familial breast cancer do not have detectable mutations in any known gene. 

A research-driven service: As our knowledge of the genetic basis of malignancy increases the approach to prevention, surveillance and treatment of cancer is also changing.  New insights into the role of modifier genes and environmental exposures provide the rationale for development of improved treatment algorithms based on molecular classification of patients with similar clinical characteristics. This goal forms the basis of a research project on breast carcinoma approved by the Ethics Review Committee of the University of Stellenbosch in December 2007 (Project number N07/07/158). Given the fact that genes determine response to drugs (pharmacogenetics) and certain nutrients (nutrigenetics), cancer prognostication and treatment guided by molecular pathology tests are likely to improve clinical outcome and compliance to cancer treatment and risk reduction strategies, at least in a subgroup of patients with specific requirements due to their genetic make-up.


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