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BRCA1 and BRCA2 gene mutations and risk of breast cancer:: Public health perspectives

https://doi.org/10.1016/S0749-3797(98)00136-6Get rights and content

Abstract

Content: Breast cancer is the most common cancer and the second most common cause of cancer death among U.S. women. In 1998, about 178,700 new cases will be diagnosed and 43,500 women will die from the disease. Mutations in the BRCA1 gene, which was cloned in 1994 and is located on chromosome 17q, have been identified as causes of predisposition to breast, ovarian, and other cancers. A second breast cancer gene, BRCA2, has been localized to chromosome 13q. Using inferential procedures, the overall carrier frequency of BRCA1 gene mutations has been estimated at 1 in 500 in the general U.S. population. Recent studies have indicated that the carrier frequency of a specific BRCA1 allele, the 185delAG mutation, may be as high as 0.8% to 1% among women of Ashkenazi Jewish descent.

Conclusions: Due to the proliferation of laboratories offering genetic tests for breast cancer susceptibility, their appropriate use in public health needs careful scrutiny. Several issues are raised when such genetic tests are considered for population-based prevention programs for breast cancer. Public health agencies, such as the Centers for Disease Control and Prevention, are important to monitoring and evaluating genetic testing done outside of research protocols. If genetic tests for breast cancer are to be incorporated into future prevention programs, evaluation is needed of whether the testing can have the intended effect.

Introduction

I n 1990, a region on chromosome 17 was associated with early-onset familial breast and ovarian cancer.1 In 1994, the BRCA1 gene was identified by using positional cloning techniques.2 A second breast cancer gene, BRCA2, was subsequently located on chromosome 13q.3 These advances led to the rapid development and commercialization of genetic tests for breast cancer susceptibility. Although recent policy statements have recommended that such testing be limited to women enrolled in research approved by institutional review boards, some women are seeking out such testing and biotechnology companies are marketing tests for BRCA1 and BRCA2 gene mutations directly to physicians.4, 5 Because of the proliferation of genetic tests for susceptibility to cancer of the breast and other sites, the appropriate use of such tests in public health needs careful scrutiny.6

In this article, we review several issues related to testing for BRCA1 and BRCA2 gene mutations, including the significance of a positive or negative test result; the public health impact of breast cancer susceptibility genes; estimates of the carrier frequency of BRCA1 and BRCA2 mutations; available intervention or prevention methods; and the impact, quality, and safety of testing for BRCA1 and BRCA2 mutations. We also provide an overview of selected ethical, legal, and social issues of breast cancer genetic testing from the perspective of public health practice.

Section snippets

Laboratory testing for BRCA1 and BRCA2 gene mutations

BRCA1 is a large gene, containing 5,592 nucleotides that, together with noncoding intervening segments (introns), are spread over about 100,000 DNA bases.7 The BRCA1 gene is composed of 22 coding exons that produce a protein of 1,863 amino acids. More than 200 variants of BRCA1 have been identified but not all have been associated with increased risk for breast cancer.5 Although most of these mutations have been identified in only one or two families, a few, including the 185delAG mutation,

Public health impact of BRCA1 and BRCA2 breast cancer genes

Breast cancer is the most common cancer among women in the United States; in 1998, about 178,700 new cases will be diagnosed and about 43,500 women will die from the disease.19 Two of the strongest risks factors for breast cancer are age and family history.20, 21 Women who have a first-degree relative with breast cancer have a twofold to threefold increased risk of developing breast cancer.20, 21, 22

Approximately 20% of breast cancer patients have a family history of the disease in a

Estimates of carrier frequency of BRCA1 or BRCA2 gene mutations in specific populations

Relatively few estimates of the carrier frequency of BRCA1 or BRCA2 gene mutations among women in the general population who do not have a history of breast cancer have been reported. Using inferential procedures, Struewing et al.35 estimated that the overall carrier frequency of BRCA1 gene mutations is 1 in 500 in the general U.S. population (95% confidence interval: 1 in 300 to 1 in 800). A similar estimate (1 in 833, or between 1 in 500 and 1 in 2000) was obtained by Ford et al.26 Such

Interactions of BRCA1 and BRCA2 gene mutations with modifiable risk factors for breast cancer

Most nongenetic risk factors for breast cancer have low predictive value, and the use of genetic tests may improve the predictive value of environmental factors. A new paradigm of the primary prevention of breast cancer could be the identification and modification of environmental cofactors that lead to clinical disease among persons with susceptibility genotypes.6 Particularly in persons with low-penetrance mutations, breast cancer may not develop in the absence of lifestyle factors, despite

Impact, quality, and safety of testing for BRCA1 and BRCA2 gene mutations

The emergence of new genetic tests, such as those for BRCA1 and BRCA2 mutations, requires the development of standards, regulations, and guidelines to ensure the accuracy and precision of the laboratory procedures.6 All clinical laboratories in the United States that provide information to referring physicians are certified under the Clinical Laboratory Improvement Act Amendments (CLIA) of 1988. With respect to genetic testing, these regulations currently address cytogenetic testing and other

Ethical, legal, and social issues

Genetic testing for breast cancer susceptibility raises ethical and social concerns related to the adequacy of informed consent, the availability and quality of pre- and post-test counseling, and the avoidance of genetic discrimination.57 Other ethical and social issues concern the cost of and access to genetic tests for BRCA1 and BRCA2 mutations, especially among women who are socioeconomically disadvantaged or uninsured.58

The disclosure of genetic test results can have psychological and

Summary and recommendations

Breast cancer is one of the most prevalent types of cancer in the western world. BRCA1 and BRCA2 gene mutations are responsible for a small but significant proportion of breast and ovarian cancers. Researchers are beginning to address issues such as the relative importance of different BRCA1 and BRCA2 gene mutations to cancer prevalence, the carrier frequency of these mutations in specific populations, and the relationship between sporadic breast and ovarian cancers and genetic mutations.

Acknowledgements

The authors are grateful to Drs. Nancy Lee, Ralph Coates, and Wylie Burke for their thoughtful comments on this manuscript.

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