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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 |
