Affiliations of authors:W. Burke, (Department of Medical History and Ethics), M. Austin (Department of Epidemiology), and Institute for Public Health Genetics, University of Washington, Seattle.
Correspondence to: Wylie Burke, M.D., Ph.D., University of Washington, Department of Medical History and Ethics, Box 357120, 1959 NE Pacific, Rm. A204, Seattle, WA 981957120.
We agree that Begg's observations concerning the BRCA1 and/or BRCA2 (BRCA1/2) penetrance studies (1) have been misinterpreted by some commentators. Begg noted wide variation in population-based estimates of penetrance, and he further noted that many studies may have overestimated penetrance because they were based on families identified through a proband with cancer. This method could select for families with other risk factors that contribute to higher cancer penetrance for BRCA1 and BRCA2 gene mutations. This important observation points to the considerable uncertainty in our current understanding of the cancer risk associated with mutations in the BRCA1 and BRCA2 genes. However, it does not rule out a clinical role for BRCA1/2 mutation testing in some families.
The families most likely to benefit from BRCA1/2 mutation testing are those with a high prevalence of breast and ovarian cancer in a pattern consistent with autosomal dominant inheritance. An example is provided by the families used in the original linkage studies that led to the discovery of the BRCA1 and BRCA2 genes; these were families ascertained on the basis of multiple cases of breast and/or ovarian cancer, with at least some breast cancer cases occurring in men or in women at an early age (24). Initial and follow-up studies of cancer penetrance in these high-risk families indicate a lifetime risk for breast cancer of greater than 80% in female family members who inherited a mutation (2,4). Begg's analysis suggests that this high penetrance may reflect the concurrent presence of two conditions: the gene mutation and one or more additional modifying factors that increase mutation penetrance. Alternatively, high penetrance could reflect the presence of specific BRCA1/2 mutations that are more penetrant than others. By either interpretation, unaffected women from such families are likely to be at high personal risk for cancer if they inherit the mutation segregating in the family. Thus, the combination of pedigree data and mutation status can be used with confidence to estimate a high lifetime risk of cancer. Even in this setting, Begg's analysis indicates the need for caution. In estimating high risk, we assume that any modifying factors promoting risk are shared by all family members at risk; however, sharing of modifying risk factors is likely to be incomplete and may explain why the cancer experience of different mutation carriers varies, even in high-risk families. For example, the age of onset of breast cancer and the likelihood of ovarian cancer appear to vary considerably, even among women from families ascertained on the basis of high rates of cancer (2,46). Nevertheless, clinicians can make a reasonable working assumption that the presence of a BRCA1/2 mutation in the setting of a high-risk pedigree indicates a substantially elevated risk for cancer and, thus, has value as a clinical test. Begg's analysis also has implications for negative test results; clinicians should be cautious about concluding that a negative test result indicates an average cancer risk in women from high-risk families, because modifying factors promoting cancer risk may still be present in the absence of the segregating mutation.
More important, Begg's analysis suggests the need for considerable caution in the use of BRCA1/2 testing when the inheritance of cancer in the family is more ambiguous. We believe the most prudent conclusion to be drawn from current data is that BRCA1/2 mutations elevate the risk of breast and ovarian cancer but that the degree of risk is difficult to quantify in the absence of other contributing data. Thus, we suggest that there is limited clinical value for BRCA1/2 testing in the absence of evidence for autosomal dominant inheritance of cancer risk in the family.
If specific modifying risk factors can be identified, it may be possible to develop more accurate risk estimates for individual patients with BRCA1/2 mutations and perhaps to develop interventions to reduce risk based on combinations of these factors and mutations. Ultimately, such research might allow us to specify evidence-based genetic testing recommendations, even in families without evidence for autosomal dominant inheritance of cancer risk. Much work remains to be done to achieve this goal, however, and the answers emerging from such research are likely to be complex. Our conclusion that ". . . a widely applicable and meaningful estimate of penetrance is unlikely" (7) reflects our expectation that more knowledge will lead to a better understanding of the variable cancer experience of women with BRCA1/2 mutations rather than to uniform penetrance estimates.
REFERENCES
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6 Diez O, Brunet J, Sanz J, del Rio E, Alonso MC, Baiget M. Differences in phenotypic expression of a new BRCA1 mutation in identical twins. Lancet 1997;350:713.[Medline]
7 Burke W, Austin MA. Genetic risk in context: calculating the penetrance of BRCA1 and BRCA2 mutations. J Natl Cancer Inst
2002;94:11857.
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