Theme ArticlesBRCA1 and BRCA2 gene mutations and risk of breast cancer:: Public health perspectives
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.
References (64)
- et al.
Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families
Am J Hum Genet
(1998) - et al.
Risks of cancer in BRCA1-mutation carriers
Lancet
(1994) - et al.
Mutations of the BRCA1 gene in human cancer
Sem in Cancer Biol
(1996) - et al.
Inherited breast cancer
Surg Clin North Am
(1996) - et al.
BRCA1 mutations in young women with breast cancer (letter)
Lancet
(1996) - et al.
Linkage of early-onset familial breast cancer to chromosome 17q21
Science
(1990) - et al.
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
Science
(1994) - et al.
Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13
Science
(1994) JAMA
(1994)- et al.
Pitfalls of genetic testing
N Engl J Med
(1996)
From genes to public healththe applications of genetic technology in disease prevention
Am J Public Health
A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene
JAMA
Population genetics of BRCA1 and BRCA2 (editorial)
Am J Hum Genet
Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel–frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families
Am J Hum Genet
BRCA1–lots of mutations, lots of dilemmas
N Engl J Med
The rapid detection of unknown mutations in nucleic acids
Nature Genetics
BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing
JAMA
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews
N Engl J Med
Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer
Am J Hum Genet
Inherited breast and ovarian cancer
Hum Molec Genet
Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2
JAMA
Cancer Facts and Figures, 1998
The association of age and familial risk in a case-control study of breast cancer
Am J Epidemiol
Genetic epidemiology of breast and ovarian cancers
Epidemiol Rev
Family history of breast cancer as a risk indicator for the disease
Am J Epidemiol
Genetic heterogeneity in breast cancer susceptibility
Acta Oncol
Familial breast cancer
Recent Results Cancer Res
Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence
Am J Hum Genet
Genetic alterations in breast cancer
Genes Chromosom Cancer
Breast and other cancers in families with ataxia-telangiectasia
N Engl J Med
Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer
J Natl Cancer Inst
Glutathione S-transferase class μ deletion polymorphism and breast cancerresults from prevalent versus incident cases
Cancer Epidemiol Biomark Prev
Cited by (39)
Ethics of screening
2008, International Encyclopedia of Public HealthRisks and benefits of population-based genetic testing for Mendelian subsets of common diseases were examined using the example of colorectal cancer risk
2005, Journal of Clinical EpidemiologyCitation Excerpt :The potential benefits and harms for this group will be very dependent on the availability, effectiveness, and potential side effects of the available interventions. Although there has been a great deal of expert commentary in the literature cautioning against the use of widespread genetic testing [29–34], there are few reports that model the potential impact of genetic testing on common diseases. Grann and Jacobson [35] recently published a model based on genetic testing for BRCA1/BRCA2 in the general population.
FISH analysis of BRCA1 copy number in paraffin-embedded ovarian cancer tissue samples
2004, Experimental and Molecular PathologyPolymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer
2003, Cancer LettersSymposium overview: Genetic polymorphisms in DNA repair and cancer risk
2002, Toxicology and Applied Pharmacology