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The Human Genome


Clinical Implications of BRCA1 and BRCA2 Genes in Hereditary Breast and Ovarian Cancer

Jill M. Kolesar, PharmD, BCPS

The American Cancer Society estimates that there will be 215,990 new cases and 40,580 deaths due to breast cancer, and 25,580 new cases and 16,090 deaths due to ovarian cancer in the United States in 2004.1 Two major genes have been associated with susceptibility to breast and ovarian cancer: breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2).2 A mutation in either of these genes confers a lifetime risk of breast cancer of between 60% and 85%, and a lifetime risk of ovarian cancer of between 15% and 40%.2 A mutation in either BRCA1 or BRCA2 accounts for approximately 2% to 3% of all breast cancers and 9% of ovarian cancers.3

Overview

Genetic linkage and positional cloning were used to identify the BRCA1 and BRCA2 loci on chromosomes 17q and 13q, respectively.2 Since their identification, numerous investigations have studied their function. The BRCA1 gene is involved in the regulation of estrogen-receptor (ER) activity, control of the G1/S and G2/M checkpoints of the cell cycle, chromatin remodeling, and the DNA repair processes.3,4

The BRCA1 protein can also interact with the BRCA2 protein.5 BRCA2 is a large protein that 0interacts directly with the key homologous recombination protein RAD51, potentially regulating its activity by controlling RAD51-binding, single-stranded DNAæan essential step in recombinationæor formation of new combinations of alleles in offspring (viruses, cells, or organisms) as a result of exchange of DNA sequences between molecules. Also, BRCA2 was recently identified as a strong candidate for the gene encoding Fanconi protein D16; Fanconi anemia is a rare, autosomal-recessive disorder characterized by progressive bone marrow failure, multiple congenital abnormalities, and an increased risk of cancer, particularly acute myeloid leukemia, but also breast cancer. As Fanconi protein D1 and the other Fanconi proteins are thought to form a nuclear complex important in DNA repair, mutations in BRCA2 (Fanconi protein D1) may result in disruptions in DNA repair that lead to chromosomal instability and the congenital abnormalities and cancers described here.

Overall, it appears that mutations in BRCA1 and BRCA2 result in a decreased ability to regulate ER activity and repair DNA, plus an accumulation of additional mutations that eventually results primarily in the development of breast and ovarian cancer, although BRCA1 and BRCA2 carriers also have an increased risk of leukemia, lymphoma, melanoma, prostate, stomach, pancreas, and colorectal cancers.7,8

BRCA1 and BRCA2 Mutations

Inheritance

Both the BRCA1 and BRCA2 genetic mutations are inherited in an autosomal-dominant manner (Figure 1a), meaning that only one copy of the gene is necessary for the phenotype or disease to occur, and that a parent with a mutant gene has a 50% probability of transmitting that gene to his or her progeny.3 This is true for both men and women. Therefore, when taking a family history of breast and ovarian cancer, it is important to remember that the BRCA1 and BRCA2 genes may be transmitted from the father’s side of the family.


Click to enlarge

 Figure 1a. Dominant Inheritance, 100% Penetrance

Penetrance is the probability of developing a disease when a mutant gene is present.3 Therefore, many individuals who carry a mutation in the BRCA1 or BRCA2 gene will develop breast or ovarian cancer, but not all (Figure 1b). The concept of penetrance is an important tool in estimating and conveying risk of disease to a patient. Factors that effect penetrance are often called gene modifiers. For BRCA1 and BRCA2, these may include other genes, the type of mutation found in BRCA1 and BRCA2, or factors that effect estrogen exposure (eg, gender, pregnancy, tubal ligation, oophorectomy, breast-feeding, use of tamoxifen, oral contraceptives, and hormone therapy). Such factors can modify the effect of the BRCA1 and BRCA2 mutations and reduce the risk of breast cancer.3 Therefore, although the patient may carry a mutation in the BRCA1 or BRCA2 genes, the actual penetrance (or lifetime risk of breast cancer) is between 60% and 85% because of these gene modifiers.2


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 Figure 1b. Dominant Inheritance, 50% Penetrance

How these factors interact and affect penetrance is largely un-known; however, population studies have demonstrated an estimated penetrance of 75% for BRCA1 and breast cancer, meaning that 75% of those who carry a mutation in the BRCA1 gene will develop breast cancer, and 36% for ovarian cancer by age 80 years.7 The penetrance for BRCA2 mutations for breast cancer is reported as 53% for men and 38% for breast or ovarian cancer in women.

Frequency

In an analysis of high-risk patients referred by their primary care physicians for genetic testing of the BRCA1 and BRCA2 genes, Frank and colleagues8 analyzed 10,000 consecutive individuals over a 3-year period and included 9,090 women, 263 men, and 647 individuals of unspecified sex; of this group, 30% were of Ashkenazi Jewish descent. All subjects were referred because of early onset of breast or ovarian cancer or a strong family history, including 4,679 with breast cancer (76 men), 584 with ovarian cancer, and 240 with both.8 Therefore, the reported frequencies of BRCA1 and BRCA2 mutations in this population are expected to be much higher, and not reflective of BRCA1 and BRCA2 mutations in a general population.

Overall, 424 different mutations were identified in the BRCA1 and BRCA2 genes. Of these 424 mutations, 212 were identified in BRCA1 and 212 in BRCA2, and they occurred at similar frequencies throughout the length of the genes, indicating the lack of mutation "hot spots." The National Human Genome Research Institute database (http://research.nhgri.nih.gov) lists more than 800 distinct mutations, polymorphisms, and variants in each gene.9

A total of 1,720 individuals (17.2%) carried at least one mutation in the Frank study.8 In addition, there were 11 individuals of Ashkenazi ancestry who carried two mutations, one each in BRCA1 and BRCA2. Overall, 20% of women with breast cancer carried deleterious mutations, with a median age at diagnosis of 40 years (range, 21 to 75 years) for women with mutations in BRCA1 and 41 years (range, 24 to 72 years) for women with mutations in BRCA2. In women with ovarian cancer, 34% carried deleterious mutations, of which 199 were in BRCA1 and 82 were in BRCA2, with a median age at diagnosis of 49 years (range, 32 to 78 years) for BRCA1-mutation carriers and 55 years (range, 27 to 79 years) for BRCA2-mutation carriers. Deleterious mutations were identified in 350 (10.6%) of 3,311 women without breast or ovarian cancer. Deleterious mutations were identified overall in 21 of 76 (28%) of the men with breast cancer, with eight mutations occurring in BRCA1 and 14 in BRCA2. Again, it should be noted that these patients were referred for genetic testing for their strong family history, so the reported frequencies of BRCA1 and BRCA2 mutations in this population are expected to be much higher and not representative of BRCA1 and BRCA2 mutations in a general population.

Only the three Ashkenazi founder mutations were evaluated initially in individuals with Ashkenazi ancestry.8 Overall, 23% of these individuals had a mutation, with 53% of the mutations occurring as the BRCA1 mutation 187delAG (also known as 185delAG), 16% as the BRCA1 mutation 5385insC (also known as 5382insC), and 31% as BRCA2 mutation 6174delT. Approximately 2% of individuals with Ashkenazi ancestry who were negative for a founder mutation carried a different BRCA1 or BRCA2 mutation when evaluated by full sequencing. Variants of uncertain clinical significance in the absence of known deleterious mutations were identified in 13% of individuals, and polymorphisms were identified in an additional 6.8%.

TESTING Recommendations

Process

Candidates.—The American Society of Clinical Oncology’s (ASCO) updated Policy Statement for Genetic Testing of Cancer Susceptibility was approved in March 2003, and is available online at www.asco.org.10 The ASCO recommends that genetic counseling and testing be offered when a patient has a personal or family history that suggests a genetic cancer susceptibility; the test can be interpreted appropriately; and the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.

A personal or family history suggesting hereditary breast or ovarian cancers, satisfying the ASCO criterion, is generally defined as a personal or family history of breast cancer before age 50 years, or ovarian cancer at any age; individuals with two or more primary diagnoses of breast and/or ovarian cancer; or male breast cancer patients. Therefore, genetic testing for BRCA1 and BRCA2 genetic mutations may be considered the standard of care for patients satisfying this criterion. Most insurance companies and Medicare provide some level of reimbursement for genetic testing in these circumstances.11

Pretest Counseling.—Adequate genetic education and counseling should be provided for all patients, regardless of whether they elect to undergo genetic testing10,12 The actual education may be carried out by a genetic counselor, the physician, or another health care provider with the requisite knowledge and training. Education and counseling should include the benefits and limitations of genetic testing. In the case of BRCA1 and BRCA2 mutations, benefits would be earlier identification of the carrier state and implementation of surveillance or risk-reduction strategies that would decrease the risk of breast or ovarian cancer. In the event the test is negative in a patient with a strong family history, the benefit would be decreased psychological stress and the absence of risk that would necessitate increased intervention and surveillance. The risks of genetic testing include psychological stress, the false-positive and false-negative rates of a given test, and the risk of insurance or employer discrimination.13-15 The genetic counseling process should culminate in the patient being fully informed prior to consenting or not consenting to genetic testing. Table 1 outlines the basic elements of informed consent for BRCA1 and BRCA2 testing.

BRCA1/BRCA 2 Testing.—In the United States, BRCA1 and BRCA2 testing is performed commercially by Myriad Genetics on a blood sample.16 Generally, 3 weeks are required for test results (Tables 1, 2).


View this table

 Table 1. Informed Consent for BRCA1 and BRCA2 Genetic Testing

View this table

 Table 2. Commercially Available BRCA Analysis and Target Population2,16,17

Results Reporting.—Results are reported by Myriad Genetics in the following manner: positive for a deleterious mutation; genetic variant, suspected deleterious; genetic variant of uncertain significance; genetic variant, favor polymorphism; and no deleterious mutation detected.8,16,17 In patients positive for a deleterious mutation, mutations are reported as deleterious if they result in a protein that is less than full size or in other mutations that are known from clinical and research studies to affect protein function. Results are classified as genetic variant, suspected deleterious if the available clinical and in vitro studies suggest that the mutation is deleterious; published evidence supporting the level of suspicion is provided with the test results. A genetic variant of uncertain significance is reported if the clinical significance is unknown. The category of genetic variant favoring polymorphism includes genetic variants that are highly unlikely to contribute substantially to cancer risk, and published evidence supporting the level of suspicion is provided with the test results. Finally, a patient’s genetic sequence that is identical to a consensus wild-type sequence or that contains a known variant with clinical evidence indicating an absence of increased risk is reported as no deleterious mutation.

Posttesting Counseling and Management.—BRCA1 and BRCA2 genetic test results are important factors in designing a prevention or surveillance plan, but must be considered in the context of patient preference and clinical factors. A patient with results indicating no deleterious mutations or a genetic variant favoring polymorphism can still have a substantial risk for breast cancer as estimated by the Gail model or other methods, especially in the presence of a strong family history. Rare variants of BRCA1 and BRCA2 mutations, other familial syndromes, or other unknown factors may be contributing to breast cancer risk.2 Therefore, a patient with a strong family history for breast cancer may still be a candidate for chemoprevention despite a negative genetic test.

Individuals with genetic variance of unknown significance should have prevention and surveillance plans designed based on individual patient characteristics. A patient with a strong family history of breast cancer may still be a candidate for chemoprevention despite an indeterminate genetic test.2

Patients with deleterious or suspected deleterious mutations in the BRCA1 and BRCA2 genes are candidates for breast cancer risk reduction strategies. Two accepted options are available to women with mutations in BRCA1 and BRCA2: surveillance or prophylactic mastectomy/oorphorectomy.2 Women who choose surveillance could consider a clinical study evaluating magnetic resonance imaging (MRI)-based screening rather than standard imaging. Several studies have shown that in women with germ-line BRCA1 and BRCA2 mutations, breast cancers are likely to occur as interval cancers, so that standard mammography may not be optimal to assess risk.18-23

Surveillance appears effective in identifying breast cancers. In one evaluation of 1,198 women at high familial risk for breast cancer (143 were subsequently identified to be BRCA1 or BRCA2 carriers), the average breast cancer detection was 8.6 per 1,000 person-years. Twenty-six of the 35 tumors were detected at screening, making the rate of screening-detected cancers 7.2 per 1,000. In the screening-detected tumors, 12 cancers were not palpable at the time of detection, and were found by mammography (n = 9) or MRI (n = 3).23

In two separate evaluations of female BRCA1 and BRCA2 carriers, between 14%24 and 54%25 of women underwent prophylactic bilateral mastectomy. In patients undergoing mastectomy, no new cancers were reported after follow-ups of approximately 1 to 3 years.

The use of tamoxifen to prevent breast cancer in carriers of BRCA1 and BRCA2 mutations remains controversial, as most BRCA1 tumors are ER-negative.2,25,26 In a subsequent analysis of the Breast Cancer Prevention Trial (BCPT), subjects at increased risk who then developed breast cancer and who were treated with tamoxifen or placebo were analyzed for BRCA1 and BRCA2 mutations; participants at increased risk were age 35 years or older with a 1.66% or greater risk of breast cancer over the next 5 years as estimated by the Gail model; had lobular carcinoma in situ; or were age 60 years or older. The investigators reported that only 17% of BRCA1 tumors were ER-positive versus 76% of BRCA2 tumors, and that tamoxifen was ineffective in preventing breast cancer in BRCA1 and BRCA2 carriers. However, the BCPT was not originally designed to evaluate the benefit of tamoxifen in this population, and the study was probably too small to detect a significant difference. As estrogen exposure is clearly a gene modifier for BRCA1, experts recommend that BRCA1 carriers consider tamoxifen therapy.2

Ovarian Cancer Risk Reduction.— Prophylactic oophorectomy is recommended for carriers of the BRCA1 and BRCA2 mutations as soon as they have completed childbearing.2,12 In BRCA1 and BRCA2 mutation carriers, prophylactic oophorectomy reduces the risk of breast cancer (via estrogen removal) by more than 60%, and of ovarian cancer by 95%.2,27-29 Surveillance regimens are not recommended, as none have been shown to decrease the number of women presenting with advanced disease.


Treatment Strategies FOR TUMORS

The primary utility of BRCA1 and BRCA2 testing is in early identification and risk-reduction strategies for mutation carriers.30 Although preliminary investigations31-33 suggest that BRCA1 and BRCA2 carriers may have more aggressive disease or a poorer prognosis, BRCA1 and BRCA2 carriers who develop breast and ovarian cancer currently receive standard therapy based on disease pathology and stage.

The optimal screening, surveillance, and treatment strategies for BRCA1 and BRCA2 carriers are currently unknown. Participation in ongoing clinical trials may be considered by all patients. The reader is referred to the US National Institutes of Health’s National Cancer Institute Web site to access current ongoing trials (http://www.cancer. gov/search/clinical_trials/).

Conclusion

The BRCA1 and BRCA2 genetic mutations are clearly implicated in the pathogenesis of hereditary breast and ovarian cancer. Discussion of BRCA1 and BRCA2 in the context of genetic counseling should be considered the standard of care for patients at risk of hereditary breast and ovarian cancers. Patients electing to undergo BRCA1 and BRCA2 genetic testing should have test results incorporated into their individualized risk reduction and prevention plans.


Jill M. Kolesar, PharmD, BCPS, FCCP, is associate professor, University of Wisconsin, School of Pharmacy and University of Wisconsin Comprehensive Cancer Center, Madison.

References
  1. American Cancer Society. Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society; 2004.
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  9. National Human Genome Research Institute (http://research.nhgri.nih.gov/bic/). Accessed August 2003.
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  28. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346(21): 1616-1622.
  29. Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002;20(5):1260-1268.
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  32. Ottini L, Masala G, D’Amico C, et al. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res. 2003;63(2): 342-347.
  33. Goffin JR, Chappuis PO, Begin LR, et al. Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer. 2003;97(3): 527-536.

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