Correspondence
Pitfalls of Genetic Testing
N Engl J Med 1996; 335:1235-1237October 17, 1996
- Article
To the Editor:
In their discussion of pitfalls of genetic testing (May 2 issue)1 Hubbard and Lewontin seriously misrepresent several issues with regard to predictive genetic testing for mutations in the BRCA1 gene, and specifically testing for the 185delAG mutation in Jews. Their view that “DNA tests cannot usually help clinicians or benefit patients” is inconsistent with the view of many experts in medical genetics. In the same issue of the Journal, Haber et al. state that the 185delAG mutation is likely to be “a fully penetrant allele” and that the lifetime risk of breast cancer in 185delAG carriers is likely to be extremely high regardless of family history.2 Testing for 185delAG is clearly useful to many women and their families and is now being offered at the University of Toronto and McGill University.3
Predictive testing for breast cancer and other cancers will soon become standard medical practice. If patients and their physicians wish to have the information that such testing can provide, and if after genetic counseling the patient clearly understands the benefits and limitations, the information should be made available.
When The New York Times reported our offer of 185delAG testing to Jewish people,4 the response of physicians and patients was overwhelmingly positive. The identification of groups at elevated risk for cardiovascular disease has been followed by major declines in mortality from cardiovascular causes, due in part to preventive action that includes surveillance and prophylactic intervention. The tools are now at hand to give some people at high risk for cancer opportunities to use preventive measures when they and their physicians deem such measures appropriate. We predict that genetic testing will result in a decline in age-adjusted mortality from breast cancer and other cancers, especially among younger people.
Testing for a predisposition to cancer must not be restricted by self-interest to the research and bioethics communities, and in a society founded on freedom and personal responsibility an informed public will ensure that this does not happen.
4 ReferencesHarvey J. Stern, M.D., Ph.D.
Anne Maddalena, Ph.D.
Joseph D. Schulman, M.D.
Genetics and IVF Institute, Fairfax, VA 220301
Hubbard R ,Lewontin RC . Pitfalls of genetic testing. N Engl J Med 1996;334:1192-1194
Full Text | Web of Science | Medline2
Haber DA ,Garber JE ,Finkelstein DM . Breast cancer and BRCA1 mutations. N Engl J Med 1996;334:1199-1200
Full Text | Web of Science | Medline3
Rosenblatt DS ,Foulkes WD ,Narod SA . Genetic screening for breast cancer. N Engl J Med 1996;334:1200-1201
Full Text | Web of Science | Medline4
Kolata G. Breaking ranks, lab offers test to assess risk of breast cancer. New York Times. April 1, 1996:A1, A15.
To the Editor:
The debate over genetic testing and cancer is partly about the role of biotechnology and insurance companies in the process. Were it not for the free-market structure of the health care system in the United States, much of the debate would be redundant. Hubbard and lewontin concentrate on this aspect of genetic testing. They state that carrying a “cancer-prone” gene “does not mean that [a woman] will definitely have a tumor, even though her lifetime risk of breast cancer may be as high as 85 percent.” No serious cancer geneticist would disagree. The authors are aware that this risk is hugely in excess of the risk in the general population. Are not women entitled to know whether they are at increased risk? Again, many cancer geneticists would agree that prophylactic or preventive surgery is an “extreme” measure, but I think many would also argue that for all their flaws, drawbacks, and uncertainties, such measures should at least be discussed with carriers. The authors state that it is hard to know how to counsel women. I agree. But is it not our job to try? Sometimes knowledge, however painful, is useful to those who ask for it.
I share Hubbard and Lewontin's anxiety about commercial pressure to perform genetic testing. Physicians caring for people with cancer, or at increased risk for it, need to be aware of the limitations of such testing. However, women who are seen by cancer geneticists because of an often shocking family history of cancer need support in facing extremely difficult decisions.
William D. Foulkes, M.B., B.S., Ph.D.
McGill University, Montreal, QC H3G 1A4, CanadaTo the Editor:
Hubbard and Lewontin raise complex and sensitive ethical questions occasioned by the bonanza of information about the human genome. We concur with them and their call for skepticism and balance. Two of their statements are misleading, however. They write that “the simplicity of the alterations in the base sequence and hemoglobin associated with sickle cell anemia has not yielded therapeutic benefits. And many DNA variants are involved in another hemoglobinopathy, β-thalassemia.”
First, understanding the molecular pathogenesis of erythrocyte sickling and its pathophysiologic complications, which range from vaso-occlusion to susceptibility to bacterial infection, has resulted in interventions that have substantially increased the average life span of persons with sickle cell disease. Moreover, knowing the fundamentals of hemoglobin-gene regulation and the effects of the expression of fetal hemoglobin on red-cell sickling has led investigators to explore strategies for increasing the production of hemoglobin F in patients with this disorder. This quest recently culminated in a national cooperative study that provided conclusive evidence of the efficacy of hydroxyurea therapy in patients with sickle cell disease.1 This treatment resulted in a decrease of 50 percent in acute pain crises, with a clear effect on the quality of life of a large number of people with chronic disease and a concomitant reduction in the cost of their medical care.
Second, regarding β-thalassemia, despite the multitude of genetic variants, techniques of safe and early prenatal diagnosis based on a detailed understanding of globin-gene structure have markedly reduced the number of babies born with this catastrophic disease.2 Furthermore, studies of the mechanisms of phenotype–genotype relations in patients with β-thalassemia, which have provided at least some information about how variability at the gene loci may modify the expression of the disease, have gone a long way toward permitting the kind of accurate predictive counseling to which Hubbard and Lewontin would aspire.
The complex issues that have arisen from our expanding knowledge of the human genome are challenges that can and will be met. As hematologists and medical geneticists who have seen molecular genetics vastly improve our ability to care for patients with chronic and often fatal illnesses, we believe it important that the benefits as well as the dangers of the new knowledge be communicated accurately to physicians and the public.
2 ReferencesH. Franklin Bunn, M.D.
Thomas P. Stossel, M.D.
Brigham and Women's Hospital, Boston, MA 02115Bernard G. Forget, M.D.
Yale University School of Medicine, New Haven, CT 06520-8021George Stamatoyannopoulos, M.D., Dr.Sci.
University of Washington, Seattle, WA 98195-7720David J. Weatherall, M.D.
University of Oxford, Oxford OX3 9DU, United Kingdom1
Charache S ,Terrin ML ,Moore RD , et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-1322
Full Text | Web of Science | Medline2
Cao A ,Rosatelli MC ,Leoni GB , et al. Antenatal diagnosis of β-thalassemia in Sardinia. Ann N Y Acad Sci 1990;612:215-225
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The first paragraph of the letter by Stern et al. exemplifies what worries us when the hypothetical benefits of genetic testing are translated into promises of positive health outcomes by people with a commercial interest in the situation. The authors begin in the classic hypothetical mode, raising the possibilities that “the 185delAG mutation is likely to be `a fully penetrant allele'” and that “the lifetime risk of breast cancer in 185delAG carriers is likely to be extremely high,” but they cannot tell us what those likelihoods are. Then, as usual, they slip from the hypothetical to the assertive, claiming in the next sentence that “testing for 185delAG is clearly useful to many women and their families. . . . ” They next state that predictive testing for cancer, which they say “will” (not “may”) soon become “standard medical practice,” is appropriate provided “the patient clearly understands the benefits and limitations.” But patients cannot clearly understand information that basic scientists and providers do not yet have. Over and over, hypothetical possibilities turn into assertions without evidence.
Both Stern et al. and Foulkes speak of women's “right to know.” We agree that women are entitled to know whatever is to be known. But research-based knowledge about the importance of gene-based predictions concerning breast cancer is limited, and effective preventive measures are lacking. Therefore, we seriously question the health or psychosocial benefits of such knowledge. And although we favor a single-payer national health service, we do not agree with Foulkes that it in itself would address the medical and psychosocial problems raised by the uncertainties inherent in genetic testing for complex, multifactorial health conditions.
Bunn et al. seem to miss two of our main points. First, there is a major difference between the predictiveness of genetic tests for conditions with patterns of so-called simple mendelian inheritance (such as sickle cell anemia) and that of tests for complex conditions involving the interplay of multiple, though perhaps partly gene-based, factors (such as cancer). Second, even in the “simplest” cases, there is no reason to expect that today's scientific understanding will produce health benefits by tomorrow morning. The fact that therapies are just now beginning to alleviate the symptoms of sickle cell disease, even though the molecular details of the disease have been understood for nearly 50 years, proves that point. One should also not confuse benefits derived from the termination of pregnancy with therapies.
Ruth Hubbard
R.C. Lewontin
Harvard University, Cambridge, MA 02138- Citing Articles (2)
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