BRCA Gene Screening

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The theory of genetic risks factors for certain cancers has been described since the time of ancient Rome. In 1866, Paul Broca, a French physician, reported ten cases of breast cancer spanning four generations of his wife’s family. Recently it has been shown that genetic predisposition accounts for five to ten percent of ovarian and breast cancers. Mary-Claire King and associates, in 1990, localized the first major susceptibility gene for breast and ovarian cancer on chromosome 17 and have referred to it as BRCA1 (BR=Breast and CA = Cancer). Since that time BRCA2, which predisposes its carriers predominately to breast cancer, has also been isolated.

BRCA is thought to be a tumor suppressor gene that codes for a protein that regulates transcription of genes involved in cellular proliferation. To date, over 100 mutations on BRCA1 which are associated with truncation of the protein have been discovered. Missense mutations, which are aberrations in the DNA that do not appear to confer any changes to the protein, have also been described, but, the clinical relevance of these changes is unclear. The “two hit” model for genetic predisposition assumes that a carrier is born with a mutation in one of the two BRCA genes, but that the normal BRCA gene imparts its protective effects until such time that the normal gene undergoes a mutation for what ever reason (e.g. environmental factor). At that point, the tumor suppressor protein is no longer encoded properly and a cancer develops.

Seven percent of breast cancers and ten percent of ovarian cancers are related to susceptibility genes, mainly BRCA1 and BRCA2. Obviously not all susceptibility genes have yet been identified. It is suspected that as many as 1,000,000 (about 0.5% - 0.6%) United States women are carriers of the altered BRCA1 or BRCA2 gene. Ashkenazi Jewish women are at particularly high risk with over 1% carrying the gene. Women that carry the mutation have an 82% risk of breast cancer and a 44% risk for ovarian cancer (BRCA1) by the age of 70. Interestingly, these women are often afflicted at a younger age with a 59% risk of breast cancer before the age of fifty, and often these patients will be afflicted with cancer before the age of 40.

The American Society of Clinical Oncology recommends that cancer predisposition testing be offered only when: 1) the person has a strong family history of cancer or very early onset of the disease; 2) the test can adequately be interpreted; and 3) the results will influence medical management. However, “strong family history” was not defined. Early studies that tested first generation relatives of cancer patients afflicted before the age of forty showed that approximately 53% had a deleterious mutation in BRCA1. If the relative was diagnosed with cancer between the age of 40 and 60, the mutation rate dropped to 16%. Therefore, determination of who should be tested should be based both on the number of relatives that were affected, and equally as important, the age at which they were affected.

Management of patients that carry the aberration of the BRCA gene is still evolving. Medical modifications, at a minimum, should include increased screening for breast and ovarian cancer, and discussions of prophylactic surgery. Lifestyle modifications should include refraining form alcohol, weight loss in the overweight patient, possible use of oral contraceptives, and cessation of smoking--all of which have been shown to have a deleterious effect on breast cancer. The use of antioxidants in this group of patients may also prove to be of benefit.

Counseling for genetic testing, as per the American Society of Clinical Oncology, should involve the following eleven points:

  1. Information on the specific test being performed
  2. Implications of positive and negative results
  3. Options for estimation without genetic testing
  4. Risk of passing a mutation to a child
  5. Technical accuracy of the test
  6. Possibility that the test will not be informative
  7. Fees involved in testing
  8. Risk of psychological distress
  9. Risk of insurance or employer discrimination
  10. Confidentiality issues
  11. Options for medical surveillance and screening following testing


Barbara L.Weber: Genetic Testing for Breast Cancer. Scientific America Science and Medicine,12-21,Jan/Feb 1996

Clause EB et al. Cancer 1996;77:2318-2324

Statement of the American Society of Clinical Oncology: Genetic Testing for Cancer Susceptibility. Journal of Clinical Oncology, Vol 14, No 5 (May), 1996: 1730-1736

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