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    BRCA1 and BRCA2: Genetic testing and intervention strategies


    Molecular Basis of Mendelian Disorders

    BRCA1 and BRCA2:
    Genetic testing and intervention strategies

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    By Andrew J. Li, MD, Ilana Cass, MD, and Beth Y. Karlan, MD

    Who should undergo genetic testing? Before ordering it, three conditions should be met: There should be a greater than 10% likelihood of a positive test; the ordering physician should be able to interpret the result; and the information should be used to make management decisions.

    Each year in the United States, breast and ovarian cancers are diagnosed in more than 200,000 women and are responsible for almost 60,000 deaths. These diseases have multiple causes. For breast cancer, risk factors include genetic predisposition, damage to breast-cell DNA by environmental or metabolic toxins such as ionizing radiation and alcohol, and epigenetic stimulation by endogenous and exogenous sex steroid hormones.1

    Epidemiologic studies suggest that high-risk women more frequently have benign proliferative breast disease and are exposed to sex hormones over a longer period of time. Examples of long-term exposure are early menarche and late menopause, and possibly estrogen and progestin hormone replacement therapy (HRT). For ovarian tumors, family history also increases risk, and other risk factors may be related to incessant ovulation and/or infertility, such as nulliparity, early menarche, and late menopause. Epidemiologic data also suggest that oral contraceptives and multiparity reduce the risk of ovarian cancer.2 While nongenetic factors may play a role in some familial clustering of these diseases, approximately 5% to 10% of all breast and ovarian cancers can be explained by the inheritance of mutations in one of the two major breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2.3

    Original reports first linked a subset of families with early-onset breast cancer to the BRCA1 locus. Subsequently, most families with hereditary breast and ovarian cancer (HBOC) have also been linked to BRCA1, including virtually all those initially believed to constitute a separate site-specific ovarian cancer syndrome. Analysis of the remaining families who did not have BRCA1 revealed a second locus to which some were linked; this was later confirmed to be BRCA2. We now know that mutations in BRCA1 and BRCA2 are responsible in up to 95% of families with HBOC.4 Although the risk for breast or ovarian cancer may sometimes be heightened in other hereditary cancer syndromes (such as Cowden's disease), no other genes, such as a putative "BRCA3," appear to be responsible for a significant proportion of HBOCs.5

    As risk assessment tools and genetic testing become more sophisticated and available, women at both high and low risk are seeking ways to reduce their chances of developing breast or ovarian cancer. The Gail model is a common risk assessment tool that estimates the probability of developing breast cancer.6 This statistical model, however, has substantial limitations: It greatly overestimates the risk of noncarriers and underestimates the risk of mutation carriers, making it currently invalid for women with hereditary risk. Furthermore, the Gail model does not identify women with risk for ovarian cancer conferred by mutations in BRCA1 and BRCA2, nor does it predict which women with breast cancer have a greatly increased risk for a second breast cancer due to mutations in these genes.7

    Thus, for a patient whose personal or family history suggests hereditary risk, make it your first step to determine whether she is a candidate for genetic testing. In this review, we will briefly discuss the biology of BRCA1 and BRCA2, examine the role of genetic testing, and assess interventions for women found to be at higher risk due to inherited susceptibility.

    The biology of BRCA1 and BRCA2

    Because the BRCA1 and BRCA2 genes encode proteins that normally function to mediate genetic integrity after DNA damage, they are known as tumor suppressor genes. When mutations in these genes occur, they disrupt their normal functions in regulating cell turnover and DNA integrity, increasing the risk of cancer. Escalating risk associated with BRCA1 and BRCA2 follows Knudson's "two-hit hypothesis" model: one mutant allele is inherited, usually in an autosomal-dominant manner, and carcinogenesis develops only after the second allele undergoes somatic loss, mutation, or epigenetic silencing, such as with methylation. The offspring of mutation carriers have a 50% chance of inheriting a mutant allele from either parent.

    Chromosonal locations. The BRCA1 gene is located on chromosome 17q21 and encodes a 1,863 amino acid protein whose exact biochemical functions remain unclear. The 7.8-kb mRNA transcript is expressed in the breast and ovary, and a "zinc-finger" motif in the protein suggests that it may function as a transcription factor.8 The BRCA2 gene, on the other hand, is located on chromosome 13q12-13 and encodes a 3,418 amino acid protein; both BRCA1 and BRCA2 share significant sequence homology.9 Mutations are located throughout both genes with little evidence for clustering or "hot spots." Most of these mutations are nonsense or frameshift alterations that result in a nonfunctional protein product. Moreover, within different populations, the frequencies of BRCA1 and BRCA2 mutations can vary widely, due to founder mutations (discussed below) or alleles that are prevalent in some ethnically isolated groups.

    While the precise functions of BRCA1 and BRCA2 remain unknown, mounting evidence suggests that these genes are involved in controlling the rate of cellular proliferation, DNA replication, and DNA repair. These tumor-suppressor activities are confirmed by retroviral wild-type transfer studies that demonstrate suppression of ovarian and breast cancer cell growth in vitro and tumorigenicity in vivo.10 The BRCA1 protein physically associates with several proteins that participate in chromatin remodeling, transcriptional activity, and DNA damage response. For example, BRCA1 binds and activates the transcription factor p53, which mediates cell cycle arrest, damage-response gene transcription, and apoptosis.11

    Role in risk for other cancers. Inherited mutations in these autosomal genes may increase the risks of other cancers in men as well as women. BRCA2 mutations confer a lifetime risk of male breast cancer estimated around 6%, as well as an increased risk of prostate cancer of approximately 20% by age 80. Both men and women with mutations in BRCA2 have an elevated risk of pancreatic cancer compared with the general population, although the lifetime risk is still low (2% to 3%).12,13 While some earlier studies indicated that mutations in these genes may also increase the risk for colorectal cancer, more recent data have not demonstrated any linkage.14

    Who should undergo genetic testing?

    Even though identification of BRCA1 or BRCA2 mutations can provide valuable information about lifestyle choices and prevention strategies, not all women are candidates for genetic testing. Hundreds of sequence variations, polymorphisms, or mutations have been identified to date in BRCA1 alone, and completely sequencing these relatively large genes would be expensive.15 Furthermore, disease-associated BRCA1 and BRCA2 mutations are rare, estimated at approximately 0.01% to 0.1% in the general public.16 With that in mind, the American Society of Clinical Oncology recommends that three conditions be met before a consenting man or woman is tested: There should be a greater than 10% likelihood of a positive test; the ordering physician should be able to interpret the result; and the information should be used to make management decisions.17

    Women with family histories that suggest a hereditary cancer should be considered for genetic testing (Figure 1). BRCA-associated cancers are distinguished by their occurrence in multiple family members within a single lineage.18 Specifically, any woman with two or more family members who developed breast cancer before age 50 or ovarian cancer at any age should be considered for genetic testing.19,20 Similarly, breast and ovarian cancer in the same woman or male breast cancer at any age may suggest a hereditary mutation. Because either parent may pass on mutations to their offspring, always investigate inheritance from the father's side for affected relatives.


    Click here to view full-size graphic


    Certain women already diagnosed with a breast or ovarian cancer should also be considered for genetic testing. A woman diagnosed at an early age with breast cancer or at any age with ovarian cancer is more likely to have mutations in these genes—and therefore is at higher risk for developing a second breast or ovarian cancer. Langston found BRCA1 mutations in five of 80 women (6%) who already had breast cancer before age 35, and Fitzgerald found BRCA1 mutations in five of 30 women (17%) diagnosed before age 30.21,22 Another report, using data from population-based studies, estimates that 2.8% of all ovarian cancers diagnosed in women younger than 70 are attributable to BRCA1 mutations.23

    Some ethnically isolated populations also have a higher risk of harboring BRCA1 and BRCA2 mutations. Perhaps the best known of these groups are Ashkenazi Jewish women of Eastern European descent. Szabo estimated that 2.0% to 2.5% of these women carry a mutation in BRCA1 or BRCA2, and 20% of Jewish patients diagnosed with breast cancer before age 40 were found to have BRCA1 mutations.24,25 Such founder mutations have been described for different ethnic populations: The two most common in Ashkenazi Jewish women, 185delAG and 5382insC, account for approximately 10% of all the mutations seen in BRCA1.26 These two mutations are ten times more likely to be seen in Ashkenazi Jews than in non-Jewish Caucasians.27,28 In the BRCA2 gene, 6174delT is also a common founder mutation, with a prevalence of 1.4% in Ashkenazi Jews.29 Founder mutations are also present in other ethnic groups. 185delAG is seen in Moroccan and Spanish families, while 5382insC and 4153delAA are found in the Russian population (Table 1).


    TABLE 1
    Some founder mutations in BRCA1 and BRCA2 genes

    Because genetic defects can occur at unusually high frequencies in isolated populations, it is not uncommon to find that these ethnic groups are at higher than average risk of exhibiting BRCA1 and BRCA2 mutations. The phenomenon, known as a founder effect, results when a mutant gene occurs in a population that was founded by a small ancestral group and multiplied by the group's isolation and the chance disappearance of the normal alternative allele.
    Families (No.)
    Jewish, Moroccan, Spanish
    5101bp deletion
    Dutch, Belgian
    Jewish, Eastern European, Russian
    Source: Olopade OI, Weber BL. Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: Part I. PPO Updates: Principles and Practice of Oncology. 1998;12:5.


    Many woman considering genetic screening have legitimate concerns that identification of a risk for HBOC may have implications for their access to affordable health insurance. Researchers asked genetic counselors themselves how they'd react to finding out they're at 50% greater risk of harboring a BRCA1 or BRCA2 mutation: While 85% said they would still pursue genetic testing, a full 68% would not bill their insurance companies, to retain anonymity. Furthermore, 26% said they would use an alias when undergoing DNA testing.30 To address this concern, the Health Insurance Portability and Accountability Act of 1996 limited the ability of group health plans to consider genetic information as a pre-existing condition or to use it to deny or limit coverage. While the fear of genetic discrimination still exists, to date no instances of insurance bias following BRCA1 or BRCA2 testing have been reported.31,32 More and more patients are requesting and obtaining coverage for the cost of genetic testing from their insurance carriers.

    Complete BRCA gene sequencing is not the only option

    After appropriate genetic counseling and consent, women may undergo testing for mutations in BRCA1 and BRCA2 with a blood sample sent by a health care professional. The most sensitive test is a complete gene sequence analysis of the entire coding sequence of the BRCA genes. While this remains the gold standard for mutation screening, it can be time consuming, cumbersome, and costly. Furthermore, examining the entire gene may reveal errors that occur due to mutations at splice sites or in noncoding intron sequences.

    Other available tests include a specific examination of the three founder mutations more commonly seen in women of Ashkenazi Jewish ancestry, as well as analysis for a specific mutation site previously identified in an affected family member. Currently, the only federally-certified facility authorized to perform this test for clinical patient care is Myriad Genetic Laboratories. This test is 99% sensitive and 99% specific for abnormalities in the sequence of the protein-coding regions of the BRCA1 and BRCA2 genes, where nearly all the clinically significant mutations occur.33

    Which interventions are the best bets for reducing mortality?

    Because testing for mutations in BRCA1 and BRCA2 is relatively new, no prospective studies exist to confirm that genetic testing reduces cancer mortality. Many of the earlier conclusions about lowering breast and ovarian cancer risk in high-risk patients were limited by the heterogeneous populations studied and incomplete information regarding genetic testing.

    Some recent data, however, indicate that specific interventions may prolong a woman's survival. Risk reduction strategies fall into three basic categories: increased surveillance, prophylactic surgery, and chemoprevention.

    Surveillance: Does breast cancer screening lower risk? Despite the cost-effectiveness and feasibility of heightened surveillance for breast cancer, its benefits in actual risk reduction are not clear. The three common breast cancer screening tools are breast self-examination (BSE), physical examination by trained personnel, and mammography (Table 2).


    TABLE 2
    Breast Ca screening recommendations for BRCA1 and BRCA2 carriers

    Intervention Provisional recommendation Age
    Breast self-exam Education regarding monthly self- exam 18–21
    Breast exam by trained personnel Annual or semi-annual 25–35
    Mammography Annual or semi-annual 25–35


    While monthly self-exams are recommended for all women, encourage those at increased risk to begin earlier in adult life, both to establish a regular habit and to gain familiarity and accuracy with normal breast tissue. Although preliminary results of two trials suggest that BSE has little impact on breast cancer mortality, neither study included women with BRCA1 or BRCA2 mutations, and longer follow up is necessary before drawing definitive conclusions.34,35 The researchers also recommended more frequent breast examination by a clinician. Sensitivity, however, is estimated to vary from 17% to 89% and is affected by the stage and size of the cancer, as well as the examiner's experience.36-38

    Finally, evidence indicates that mammographic screening in women over age 50 can reduce breast cancer mortality by 25% but these findings are based on studies of women at average risk.39 Mammography for high-risk women should begin at ages 25 to 35, but women should be counseled about the potential risks, including radiation exposure and false-negative or false-positive test results. Magnetic resonance imaging (MRI) of the breast is evolving as a sensitive new modality for detection and screening; while early data demonstrate its efficacy, it remains time consuming and expensive.40

    Surveillance: Effectiveness of ovarian cancer screening. For ovarian cancer surveillance, annual or semiannual screening using transvaginal ultrasound (TVS) and serum CA-125 levels is recommended for BRCA mutation carriers, although the effectiveness of these modalities has not been confirmed (Table 3).41 A recent report raises the possibility that TVS screening, when performed annually, may allow clinicians to detect ovarian cancer at an earlier stage; however, these findings are limited by the heterogeneous population studied.42 Although screening with CA-125 levels remains the most widely used biomarker for detecting ovarian cancer, its poor sensitivity and lack of specificity are well known.


    TABLE 3
    Ovarian Ca screening recommendations for BRCA1 and BRCA2 carriers

    Intervention Provisional recommendation Age
    Transvaginal ultrasonography Annual or semi-annual 25–35
    Serum CA-125 level Annual or semi-annual 25–35


    For women at higher risk, the role of these screening modalities may be even more limited. In a study that examined the cancers arising during a familial ovarian cancer screening program, neither TVS nor CA-125 testing was effective in screening for multifocal peritoneal serous papillary carcinoma, which may be a phenotypic variant of BRCA1 and BRCA2 ovarian cancers.43 Other circulating markers may prove to be more useful; a preliminary report suggests that plasma lysophosphatidic acid (LPA) levels may be elevated in ovarian cancer patients, even in early stage-I disease.44 Studies are now evaluating this marker as a screening tool in a larger multicenter cohort.

    Surgery can reduce risk. Surgical intervention for BRCA mutation carriers is more invasive, but studies have demonstrated its efficacy in reducing cancer risk. While bilateral prophylactic mastectomy is perhaps too drastic a step for many women, the surgery can reduce the risk of death from breast cancer by 90%. In fact, a woman with BRCA mutations who undergoes this procedure can expect to live 2.9 to 5.3 years longer, depending on her cumulative risk for cancer.45,46 Additional evidence suggests that a BRCA-mutation carrier who undergoes a prophylactic bilateral oophorectomy can also halve her risk for developing breast cancer, even if she should subsequently use HRT.47

    Oophorectomy is approximately 90% effective in reducing the incidence of ovarian cancer in mutation carriers.48 While this estimate may be conservative and the expected benefit of prophylactic surgery underestimated, women must still be counseled regarding the well-described occurrence of peritoneal cancer after oophorectomy.

    Chemoprevention strategies. Current chemoprevention for breast cancer involves tamoxifen and possibly raloxifene, which belong to a class of nonsteroidal antiestrogens known as selective estrogen receptor modulators (SERMs). After tamoxifen was found to decrease the incidence of breast cancer by 45%, an FDA advisory panel recommended its use in reducing the breast cancer risk of high-risk women in September 1998.49 The use of tamoxifen in BRCA1 and BRCA2 mutation carriers, however, remains uncertain.

    Raloxifene is a newer SERM with a different spectrum of tissue-specific estrogen receptor activity. Researchers examined data from 10,500 women in placebo-controlled trials that were originally designed to evaluate bone loss. Looking this time for changes in the incidence of breast cancer, they found that raloxifene reduced the breast cancer incidence by 50%.50 As breast cancer reduction was not a primary end point of the study, however, no definitive conclusions could be drawn. Furthermore, no researchers have investigated its use in women with BRCA mutations. Presently, the Study of Tamoxifen and Raloxifene (STAR) is accruing high-risk postmenopausal women to be randomized to treatment with raloxifene or tamoxifen; results are not expected until 2006.

    OCs are known to protect against ovarian cancer in general. In a report comparing OCs in a cohort of women with BRCA1 or BRCA2 mutations, duration of use was found to reduce risk. Specifically, using OCs for 6 or more years was associated with a 60% reduction in risk.51 While prescribing OCs should be considered for women with BRCA mutations who have not had ovarian cancer, specific formulations or the age at which treatment should begin is not clear. Furthermore, the effect of OCs on increased risk for breast cancer is poorly defined in women with BRCA1 or BRCA2 mutations, and no data exist at the moment to define it.52


    As the biology of BRCA1 and BRCA2 mutations becomes more clearly defined, clinicians will be able to more accurately discuss a woman's chances of developing breast and ovarian cancer. While not all individuals are candidates for genetic testing, those you've assessed as high risk should be comprehensively counseled regarding the risks and benefits of genetic testing. Several prevention strategies, including clinical, surgical, and medical interventions, are available to reduce risk. Even though these methods remain limited and invasive, hereditary risk assessment can improve health care and the morbidity and mortality associated with these diseases. While recent advances in more effective therapeutic modalities have been important steps in the fight against breast and ovarian cancers, prevention and early detection are the ultimate goals in reducing mortality and morbidity.


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    Contemporary OB/GYN's "Genetics: Molecular Basis of Mendelian Disorders" offers readers short overviews on Mendelian disorders for which molecular progress recently has been made. The department's focus is on practical implications for ob/gyns, particularly in carrier detection and prenatal genetic diagnosis.

    Joe Leigh Simpson, MD, Series Editor
    Ernst W. Bertner Chairman and Professor
    Department of Obstetrics and Gynecology
    Professor, Department of Molecular and Human Genetics
    Baylor College of Medicine
    Houston, Tex.


    Dr. Li is a Fellow in Gynecologic Oncology; Dr. Cass is an Assistant Professor of Obstetrics and Gynecology, UCLA/Cedars-Sinai Medical Center, Los Angeles, Calif.; and Dr. Karlan is Associate Professor of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, and Director, Division of Gynecologic Oncology, Cedars-Sinai Medical Center, Los Angeles, Calif., where she also holds the Board of Governors' Endowed Chair in Gynecologic Oncology.


    Ilana Cass, Beth Karlan, Andrew Li. BRCA1 and BRCA2: Genetic testing and intervention strategies. Contemporary Ob/Gyn 2001;7:83-95.

    Andrew John Li, MD
    Dr. Li is a Fellow in Gynecologic Oncology
    Beth H. Karlan, MD
    Dr. Karlan is Associate Professor of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, and Director, Division of ...
    Ilana Cass, MD
    Dr. Cass is an Assistant Professor of Obstetrics and Gynecology, UCLA/Cedars-Sinai Medical Center, Los Angeles, Calif.


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