Affiliations of authors: P. D. P. Pharoah (Cancer Research UK Department of Oncology), A. Antoniou, D. Easton (Cancer Research UK Genetic Epidemiology Unit), University of Cambridge, Strangeways Research Laboratories, Cambridge, U.K.; J. Hopper, Centre for Genetic Epidemiology, Department of Public Health, The University of Melbourne, Melbourne, Australia.
Correspondence to: Paul D. P. Pharoah, M.R.C.P., M.F.P.H.M., University of Cambridge, Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, U.K. (e-mail: paul.pharoah{at}srl.cam.ac.uk).
A recent article by Begg (1) discusses the published estimates of risks of cancer in women who carry a mutation in BRCA1 or BRCA2. Most estimates are based on studying the risks to relatives of women with breast or ovarian cancer who are known carriers. Begg argues that such estimates will be biased, in the sense that they do not reflect the average risks to all carriers in the population. This hypothesis would be correct if the cancer risks in carriers are modified by other genes (or other familial risk factors) or if some mutations confer higher risks than others. The existence of some familial risk modification appears likely (2), and there is some evidence for variation in risk by site and type of mutation (3). Under these circumstances, risk estimates from studies of carriers who have either a strong family history of breast cancer or have breast cancer themselves will, on average, be higher than risk estimates from studies of carriers without these characteristics.
However, the conclusions drawn by Begg have been interpreted by commentators as implying that the existing estimates of risk are grossly misleading and that one cannot draw any useful conclusions about the risks in women with a BRCA1 or BRCA2 mutation. For example, the Lancet reported that "The lifetime risk of developing breast cancer in individuals who have the BRCA1 and BRCA2 mutations might have been exaggerated in previous studies . . ." (4). Similarly, the British Medical Journal stated that "Many peopleincluding some doctorsmistakenly believe that women who carry mutations in breast cancer genes BRCA1 and BRCA2 have a high risk of developing breast cancer" (5). Finally, the editorial that accompanied the Begg article in the Journal concluded that ". . . a widely applicable and meaningful estimate of penetrance is unlikely" (6). We believe that these interpretations are incorrect.
Perhaps the problem stems from a persistent use in the literature of the expression "the penetrance" [e.g., see (6)], as if there were a single entity that all studies are trying to estimate. Each study is estimating the average risk to carriers relevant to the subpopulation being studied (3). That these estimates might differ from one another does not invalidate them; rather, it gives new scientific information.
In practice, a counselor is rarely interested in the risks to the "average" carrier. Virtually all genetic testing is conducted on women in families with multiple cases of the diseasethe types of families from which the original penetrance estimates were derived. Some women are tested on the basis of having weaker family histories or of having early-onset disease; risk estimates derived by studying the cancer incidence in relatives of population-based series of women with breast or ovarian cancer may then be more appropriate. Because one affected relative would usually represent an absolute minimum criterion for genetic testing, it seems unlikely that risk estimates that lie much outside this range will be needed in any practical situation.
We agree with Begg that risk estimates to carriers should, if possible, incorporate information on modifying factors. Indeed, a risk model along these lines to incorporate the effects of other genes that can predict risk in any type of family has now been developed (2). Studies of cancer risks in relatives of cancer patients will remain the primary source of data for deriving such models.
REFERENCES
1 Begg CB. On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst
2002;94:12216.
2 Antoniou AC, Pharoah PD, McMullen G, Day NE, Stratton MR, Peto J, et al. A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 2002;86:7683.[CrossRef][Medline]
3 Hopper JL. Genetic epidemiology of female breast cancer. Semin Cancer Biol 2001;11:36774.[CrossRef][Medline]
4 Frankish H. Studies exaggerate risk of breast cancer. Lancet 2002;360:623.[Medline]
5 Minerva. Br Med J
2002;325:502.
6 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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