EDITORIAL

Genetic Risk in Context: Calculating the Penetrance of BRCA1 and BRCA2 Mutations

Wylie Burke, Melissa A. Austin

Affiliations of authors: W. Burke (Department of Medical History and Ethics), M. A. Austin (Institute for Public Health Genetics), University of Washington, Seattle.

Correspondence to: Wylie Burke, M.D., Ph.D., Department of Medical History and Ethics, Box 357120, University of Washington, 1959 NE Pacific, Rm. A204, Seattle, WA 98195 (e-mail: wburke{at}u.washington.edu).

With advances in genetic research, many experts anticipate an era of "personalized medicine," in which knowledge about genetic risk will be used to guide preventive health care, drug choices, and disease management (13). This approach may hold particular promise for cancer, because information about a genetic susceptibility could provide valuable opportunities to tailor cancer screening and prevention strategies and to refine clinical and behavioral interventions to reduce cancer risk. However, this paradigm calls for genetic tests that provide accurate risk predictions, a goal that may be far from easy to achieve.

The BRCA1 and BRCA2 genes are an important case in point. Several studies have estimated the penetrance of BRCA1 mutations, that is, the likelihood that breast or ovarian cancer will occur when a deleterious mutation is present. Nearly all conclude that cancer risk is elevated when a BRCA1 or BRCA2 mutation is present—but the estimates of risk vary widely. Initial studies suggested that the breast cancer risk was close to 90% by the age of 70 years. This estimate was based on the study of "high-risk" families, ascertained on the basis of multiple cases of ovarian or early-onset breast cancer (4). Subsequent studies that used less selected populations have provided lower and widely varying estimates, ranging in the case of BRCA1 mutations from 45% to 68% (510). For BRCA2 mutations, one study (9) found no statistically significant evidence of an increased risk for breast cancer (relative risk = 1.2, 95% confidence interval = 0.45 to 3.3 for female first-degree relatives of women with BRCA2 mutations and ovarian cancer), whereas others (58,10,11) estimated penetrance in a range from 26% to 74%. All estimates generated wide confidence intervals, indicating considerable uncertainty about the absolute magnitude of risk.

This range of risk is daunting for women considering preventive interventions with serious personal consequences or associated health risks, such as prophylactic mastectomy, prophylactic oophorectomy, or tamoxifen chemoprevention. Further, uncertainty about penetrance makes the effectiveness of these interventions difficult to measure. In the face of uncertainty about cancer rates, a definitive assessment of the benefit (and potential harm) of preventive interventions would require randomized controlled trials. Yet given the evidence for increased risk in women with BRCA1 or BRCA2 mutations, even though it is imprecise, such trials would likely be difficult to implement and would pose difficulties in the design of appropriate comparison arms.

The study by Begg (12) in this issue of the Journal provides a useful analysis of the array of penetrance estimates associated with BRCA1 and BRCA2 mutations. His analysis helps to explain the variation in results from the available studies and provides some guidance to their interpretation, but his study does not provide a simple answer for clinicians, patients, or public health professionals. Rather, he argues persuasively that a widely applicable and meaningful estimate of penetrance is unlikely.

Begg suggests that most of the available studies of BRCA1 and BRCA2 mutation penetrance are biased toward elevated risk. At the heart of his analysis is the demonstration that penetrance studies can introduce important biases when they use patients with breast cancer as their starting point, as most studies have done. These biases occur because women with breast cancer, including those identified through population-based recruitment, represent a population enriched for other risk factors contributing to breast cancer. To the extent that these risk factors modify the effect of the BRCA1 and BRCA2 mutations, studies based on patients with breast cancer and their biologic relatives lead to amplified estimates of penetrance. A similar concern arises for studies based on ovarian cancer cases, another approach used in some BRCA1 and/or BRCA2 penetrance studies. The critical question in assessing this analysis is whether the risk associated with BRCA1 and BRCA2 mutations is indeed modified by other genetic or environmental factors.

There is reason to think that it is. Phenotypic variation is commonly observed among many apparently simple single-gene conditions (13,14). Some variation is due to the different functional effects of specific gene mutations, but differences in clinical outcome also occur among people with the same mutation, indicating the presence of modifying factors that are likely both genetic and environmental. Established nongenetic risk factors have been shown to influence the outcome of genetic risk in some settings. In familial hypercholesterolemia and other genetic conditions that predispose people to coronary heart disease, for example, smoking, diet, and exercise can modify the clinical course of the disease and risk for coronary heart disease, even among family members who share the same genotype (1518).

Do these considerations apply to BRCA1 and BRCA2 mutations? Clinical outcome is heterogeneous among women with BRCA1 and BRCA2 mutations: Some women develop early and multiple cancers, whereas others develop cancer late in life or not at all. Emerging evidence suggests that established risk factors for breast cancer, such as reproductive history, may influence cancer risk among women with BRCA1 or BRCA2 mutations, although these risk factors may not operate among mutation carriers in the same way as in the general population (1923). The influence of environment is also suggested by changes in penetrance over time among women from BRCA1 and/or BRCA2 families: Cancer risk is higher for women in recent birth cohorts than it is for women in earlier cohorts (20,22). Similarly, data on possible genetic modifiers of the penetrance of BRCA1 and BRCA2 mutations are emerging (2325). It is likely that there exist many genetic contributors to breast cancer risk other than BRCA1 and BRCA2 (26,27) and that variants of these genes represent a further pool of potential modifiers to investigate.

The problem of how best to conceptualize and study interactions between genetic and environmental risk factors, as well as gene–gene interactions (epistasis), is just beginning to attract the attention of biostatisticans, epidemiologists, and statistical geneticists. As in all epidemiologic studies, interaction can be characterized as additive or multiplicative, and several different patterns of gene–environment interaction can be postulated (28), posing complex analytic challenges. These challenges are magnified when several genetic and environmental risks need to be taken into account. Yet Begg's analysis underscores the pitfalls of failing to address this complexity and its implications for disease prevention.

Will the effort to characterize the range of factors contributing to genetically influenced disease susceptibility help clinicians, their patients, and the public? With identification and careful analysis of modifiers, reliable population estimates of penetrance may ultimately be obtained for BRCA1 and BRCA2 mutations. Nevertheless, the picture is likely to remain complex, particularly for the individual patient at risk: Clinical outcomes will be difficult to predict with certainty because of the varying effects of different mutations and modifying factors. For at least some patients with deleterious BRCA1 and BRCA2 mutations, greater knowledge about modifying factors may lead to new interventions to reduce risk. The most important implication of penetrance studies, however, should perhaps be to temper our expectations for predictive genetic tests. Without a healthy respect for the many factors that may influence penetrance, we will continue to overestimate the risk conferred by BRCA1 and BRCA2 mutations alone and, thus, miss opportunities to develop truly effective prevention strategies for women who are genetically susceptible to breast cancer that are based on a broad understanding of causative factors.

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