What is a BRCA gene?
How were the BRCA genes found?
Why are Ashkenazi Jewish women especially at risk?
Why was the breast cancer predisposition gene test created?
Why undergo genetic counseling and BRCA testing?
Who can be tested for BRCA mutations?
What can the test tell me?
What is my risk if I am a BRCA carrier?
What can I do if I am a BRCA mutation carrier?
The details of BRCA testing?
What is a BRCA gene?
A functioning BRCA gene prevents tumor growth by limiting cell division. Every cell in the body has two copies of each gene. Individuals predisposed to breast cancer are born with a mutation in one of their two copies of a BRCA gene. For breast cancer to occur, both BRCA copies must be mutated. Once a second BRCA mutation is acquired, the cell divides uncontrollably, resulting in a tumor. Individuals beginning life with one mutated BRCA gene are pre-disposed to breast cancer development because their cells have only one safety belt (1 normal BRCA gene) to prevent mass cell division. Non-breast cancer predisposed individuals have two safety belts (2 normal BRCA genes) at birth and, thus, have a lower risk of developing a breast tumor.
How were the BRCA genes found?
The localization of BRCA1 and BRCA2 within the human genome enabled the creation of the breast cancer predisposition genetic tests. The BRCA genes were decisively identified as loci for breast cancer development upon mutation through genetic research involving 237 large, breast cancer-affected families. The BRCA1 and BRCA2 genes were pinpointed to chromosome 17 and chromosome 13 in 1994 and 1995 respectively.
Why are Ashkenazi Jewish women
especially at risk?
Ashkenazi Jewish women display a particularly high prevalence of breast cancer. The localization of BRCA 1 and BRCA2 has enabled the realization that three mutations may be the cause of one-third of breast cancer cases in Ashkenazi Jewish women under the age of forty. High rates of particular genetic mutations among withdrawn populations such as the Ashkenazi Jews can be explained by the founder effect. The founder effect is predominant among culturally or geographically isolated groups and is apparent when single mutations are linked to genetic transmission in the majority of occurrences.
Why was the breast cancer
predisposition gene test created?
As stated by Gauthier-Villars, Gad, Caux, et al., “it must be remembered that the main purpose for breast cancer predisposition testing is to provide women at high risk with better supportive care. Today, a major challenge for clinical research is to identify the modalities for prevention that will allow reduction of the morbidity and the mortality
linked to a high predisposition to breast cancer” (Gauthier-Villars, Gad, Caux, et al., 1171).
Why undergo genetic counseling
and BRCA testing?
According to Lerman, Seay, Balshem, and Audrain, healthy female relatives of individuals with ovarian or breast cancer tend to exaggerate their risk of incurring either form of cancer and, thus, accurate risk assessment is essential to quality genetic counseling for breast cancer. Breast cancer genetic counseling serves the goal of helping women to analyze their own and their relatives’ risk of developing breast cancer.
In BRCA screening, genetic counselors offer services in compiling family histories, personalizing epidemiology, and, more recently, conducting genetic testing to empower healthy women of families stricken by breast cancer to alter their lifestyles and healthcare to ensure avoidance or early detection of breast cancer. In addition, breast cancer victims and healthy members of a single family can enable accurate screening of female family members by obtaining a sequence of their BRCA genes. Detection of a familial BRCA mutation in individuals outside of the Ashkenazi Jewish population requires time-consuming genetic analysis of a large number of affected and unaffected family members in order to identify the specific BRCA mutation for a particular family.
Who can be tested for BRCA
The BRCA tests are currently offered only to individuals with at least a 20% likelihood of carrying a well-defined mutation in BRCA1 or BRCA2. In order for predisposition testing to occur, the familial mutation must already be well characterized by sequencing the BRCA genes of affected and unaffected family members. A first-degree relative of a carrier of a BRCA1 or BRCA2 mutation, whether mother, daughter, or sister, generally faces a 50% risk of combating breast cancer in the course of her lifetime.
Numerous medical and
genetics organizations have released suggestions to guide the process of testing
for the presence of a mutation in the BRCA loci, including the American Society
of Clinical Oncology (ASCO), the American Society of Human Genetics (ASHG), the
National Society of Genetic Counselors (NSGC), the task force
the Cancer Genetics Studies Consortium (CGSC) of National Human Genome Research Institute, the task force of the National Institutes of Health--Department of Energy, and the French National Institute of Health and Medical Research.
These organizations agree that testing for a BRCA1 or BRCA2 mutation, as with any well-defined genetic mutation, requires the informed consent of the individual to be tested after extensive counseling as to the epidemiology of the mutation of interest, the family history of the individual, and the potential impact of test results, including mental, physical, and insurance discrimination effects. In addition, children should not be tested for BRCA mutations.
The advisory organizations disagree, however, on the appropriate professionals to conduct predisposition screening and on notification of family members of genetic test results without the consent of the tested individual. The ASHG and other groups believe that only genetic counselors or geneticists should conduct testing and that relatives have the right to genetic test results if the course of the familial disease may be improved or avoided by more rigorous screening and monitoring. The ASCO, in contrast, demands that clinical oncologists also be allowed to perform BRCA tests and that the tested individual’s permission be obtained prior to release of any results. The groups agree that relevant professionals from a variety of fields should be consulted, including psychologists, radiologists, surgeons, geneticists, and oncologists.
What can the test tell me?
Testing positive or negative for a BRCA mutation is simply a risk assessment, not a certainty of experiencing or avoiding, respectively, breast cancer. Individuals with a BRCA mutation have an 80% risk of developing breast cancer by age 80. Therefore, 20% of BRCA mutation carriers never develop breast cancer. A first-degree relative of a carrier who tests negative for the mutation has the same breast cancer risk as women of the general population, namely 11%, down from the 50% estimated likelihood.
What is my risk if I am a BRCA
Mutations in either BRCA1 or BRCA2 account for about two-thirds of all familial breast cancer occurrences, with BRCA1 variation causing 28% and BRCA2 responsible for 37%. Women who carry either BRCA mutation have a roughly eight in ten likelihood of developing breast cancer by the age of seventy. Mutation of the BRCA1 gene and, to a lesser extent, BRCA2, also predisposes women to ovarian cancer. BRCA1 has been associated with 80% of familial ovarian and breast cancers with 15% occurring with BRCA2 mutation, thus accounting for 95% of all familial concurrent ovarian and breast cancers.
The resultant breast cancer forms of BRCA1 and BRCA2 mutations can be distinguished on the basis of prevalence of medullary tumors and tubule formation. Both BRCA1 and BRCA2-related breast tumors commonly invade the duct system and “…exhibit poor histologic grade,” BRCA1 is linked to medullary tumors and extremely rapid division of cells while BRCA2 tumors feature “…a low rate of tubule formation rather than a high mitotic index” (Gauthier-Villars, Gad, Caux, et al., 1175). Studies of familial breast cancer have yielded mixed results on the prognosis of BRCA1- and BRCA2-linked breast cancers relative to non-familial breast cancers.
What can I do if I am a BRCA mutation
Women with a high risk of breast cancer development can enhance their likelihood of avoiding breast cancer by engaging in one or more of the following treatment options: rigorous cancer surveillance, prophylactic mastectomy, prophylactic oophorectomy, and chemoprevention via Tamoxifen treatment.
Experts and patients alike have reached consensus that increased surveillance is essential for high-risk women. BRCA carriers 25 years of age and older should be seen twice yearly by a specialist and obtain a mammogram annually. In contrast to more invasive alternatives, heightened breast examination avoids tissue removal and harmful side effects for individuals who never incur breast cancer. Unfortunately breast cancer develops in 80% of BRCA mutation carriers and the value of surveillance depends on the patient’s long-term cooperation.
Probably the greatest debate for BRCA mutation carriers is whether or not to undergo a prophylactic mastectomy in order to reduce risk of breast cancer development, the effects of radiation and chemotherapy if diagnosed, and the mental stress of impending development of breast cancer. Prophylactic mastectomy, as a major appearance-altering surgery, poses negative effects, such as significant mental stress, including feelings of lost femininity and beauty, as well as the possibility of complications in surgery. The tissue loss inherent in prophylactic mastectomy is irreversible. In addition, prophylactic mastectomies reduce but do not remove the likelihood of breast cancer. High-risk women are, however, 90% less likely to experience breast cancer following removal of both breasts.
Prophylactic oophorectomy, or removal of the ovaries, is an additional choice for women with a high risk of breast cancer because exposure to ovary-derived estrogen enhances risk of breast cancer. If conducted before age 40, this procedure reduces breast cancer risk by 50% in comparison with natural menopause for both BRCA1 carriers and women in the general population. Oophorectomy allows high-risk patients to maintain breast tissue but forces early menopause. Unfortunately, post-oophorectomy hormone replacement therapies may enhance a woman’s risk of uterine cancer or breast tumor development.
Subjecting BRCA carriers to prophylactic chemotherapy and radiotherapy has yielded conflicting results and carries uncertain side effects, especially for young women. Treatment of high-risk women with Tamoxifen, an agent that interferes with estrogen, has, in some studies, been shown to lower the risk of breast cancer occurrence in high-risk patients in the course of treatment but post-treatment preventative value is still unclear. In addition, although participants do not sacrifice tissue, those over the age of fifty suffer increased risk of uterine cancer, blood clots, and cataracts with Tamoxifen treatment.
The details of BRCA testing?
Finding an altered portion of the BRCA1 or BRCA2 gene can take several weeks and BRCA testing may be expensive and/or not covered by health insurance. In addition, tested individuals should consider not informing their insurance companies in order to avoid rate hikes with finding of a mutation (insurance discrimination).
For more information on genetics of breast cancer and genetic screening click here
Burke W, Daly M, Garber J et al. AMA Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA 1997; 277(12):997-1003.
Gauthier-Villars, M, Gad, S, Caux, V, et al. Breast cancer management. Genetic testing for breast cancer predisposition Surgical Clinics of North America 1999; 79(5): 1171-1186.
Hartmann, LC, Sellers, TA, Schaid, DJ, et al. Breast cancer management. Clinical options for women at high risk for breast cancer. Surgical Clinics of North America 1999; 79(5): 1189-1206.
Editorial Related to Chapter 67. The genetics of common,
adult-onset diseases and testing for those at risk. http://www.harrisonsonline.com/server-java/Arknoid/harrisons/1096-7133/Updates/Editorials/?Up=edl1767
Lerman C, Seay J, Balshem A, Audrain J. Interest in genetic testing among first-degree relatives of breast cancer patients. American Journal of Medical Genetics 1995; 57:385-392.
Longo, DL. Update to
Chapter 84. Genetic screening for breast cancer