Human genome project and cancer: The ethical implications for clinical practice

Human Genome Project and Cancer: The Ethical Implications for Clinical Practice Tamsen L. Bassford and Lynn Hauck

HE HUMAN Genome Project will have farreaching effects on health care practice. By providing a "guidebook" to the 50,000 to 100,000 genes that determine healthy function in the human organism, the project will advance not only diagnosis and treatment of classic inherited disorders but also will profoundly affect our approach to more common diseases with familial components, such as cardiovascular disease, diabetes, and cancer. Although improved treatment through gene therapy and advances in biochemical therapy will be the eventual result of the project, a more immediate effect will be observed in identification of high-risk individuals for intensive screening and risk-factor modification. The initial focus of the Human Genome Project at the Department of Energy was on the effects of radiation on normal (deoxyribonucleic acid) DNA. This focus broadened with the involvement of the National Institutes of Science in 1986. t Construction of a genetic and physical map of all 46 human chromosomes is expected to be completed by 1995. By the project's end in 2005, sequencing of the 50,000 to 100,000 genes that code for proteins should be completed, t

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GENE BIOLOGY

The genetic code is carried in the sequence of the four bases (adenine, thymine, quanine, and cytisine) that form DNA. Ten percent of these, as gene sequences, actually code for protein products. 2 Some of the remaining DNA regulates these genes by turning them off and on in response to specific stimuli. Mapping refers to locating genes of clinical inFrom the Department of Family and Community Medicine, and the Department of Pediatrics, College of Medicine, University of Arizona, Tucson, AZ. Tamsen L. Bassford, MD: Assistant ProJessor, Department of Family and Community Medicine; Lynn Hauck, MA: Senior Genetic Counselor, Department of Pediatrics. Address reprint requests to Tamsen L. Bassford, MD, Assistant Professor, 1450 N Cherry Ave, Tucson, AZ 85719. Copyright 9 1993 by W.B. Saunders Company 0749-2081/93/0903-000255.00/0

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terest. Physical mapping locates a trait to a specific part of the chromosome. 3 The lowest resolution form of physical mapping occurred in 1959 when French geneticist Jerome Lejeune related Down's syndrome to the presence of an extra chromosome? In order to locate a gene to a specific chromosome, chromosomes must be distinguished from one another. This is accomplished by a technique called banding, in which staining patterns are distinctive for each chromosome. A gene can be located to a specific region of a chromosome in a variety of ways. Sometimes a clinical syndrome is associated with a naturally occurring deletion of a specific part of a chromosome. Fluorescent DNA probes and restriction fragment length potymorphisms (RFLPs) are also used to help locate the position of a gene) RFLPs are fragments of DNA formed by restriction enzymes. They vary in length among individuals because of differences in the specific bases at the cutting sites. Fragments of different lengths can be separated by gel electrophoresis. RFLPs are not associated with disease but can be inherited with a gene known to cause a disease if they are located close together on a chromosome. 3 The closer together on a chromosome two genes are located, the more frequently they are inherited together because there is less chance for "recombination" during meiotic cell division. By analyzing how frequently two traits are inherited together, one can create a linkage map. This is called genetic mapping. If the location of one trait is known, then linkage mapping can provide the approximate location of a second trait. Two traits inherited together 99% of the time (a 1% recombination rate) are said to be 1 cM (centimorgan) apart on a chromosome. In physical mapping terms? this is equivalent to approximately 1 million base pairs. Sequencing gives us the actual order of base pairs in a given gene. Sequencing methods create a set of DNA fragments whose lengths are directly related to the position of each base in the sequence. The fragments are separated according to weight and length by gel electrophoresis. In this way, the base sequence is determined. 2 Seminars in Oncology Nursing, Vol 9, No 3 (August), 1993: pp 134-138

HUMAN GENOME PROJECT'S ETHICAL IMPLICATIONS

GENETICS AND CANCER

Cancer results from a genetic event or events in a somatic cell. In most cases, a given cancer is thought to be derived from a single mutant cell. According to the multi-hit theory, malignant change results from a series of genetic events on the cellular level. 4 In the case of a familial predisposition to cancer, a germline mutation is one of two or more mutations necessary for the malignant change. As all the cells in the body then carry one of the mutations for cancer, the chances are greater that a somatic cell will undergo enough subsequent changes to become malignant. Genetic-mapping methods such as those just described have already located genes involved in several genetic cancer syndromes. The gene responsible for hereditary retinoblastoma has been located on chromosome 13, and the actual gene was cloned in 1986. 4 Its protein product is involved somehow in the control of cell division. 4 Ninety-five percent of those with this germline mutation will develop the cancer by the age of 5 years. Examinations every 4 to 6 weeks and prompt treatment of lesions can salvage the eye and lead to almost 100% survival. 5 Familial adenomatous polyposis (FAP or APC) is an autosomal dominant inherited disease in which affected people develop hundreds of adenomatous polyps in their colons. These polyps are the precursor lesions of colon cancer. Affected individuals develop polyps in their teens and colon cancer(s) in their 20s or 30s. This gene was cloned in 1991 after localization to the long arm on chromosome 5. 5,6 Currently, beginning in their late teens, members of FAP families all undergo endoscopic surveillance. Genetic testing could eliminate the need for this invasive screening in family members found not to carry the mutation. Linkage analysis with a naturally occurring polymorphism has located the gene for early onset familial breast cancer. The gene was mapped to band 21 on the long arm of chromosome 17. 7 Genetic counseling for this syndrome is currently based on determining which variant of the polymorphism is associated with the breast cancer trait in a particular family and then examining family members for that variant. There are limits to counseling based on linkage analysis: (1) the family must be large enough; (2) the family must have enough nonaffected older women; (3) genetic ma-

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terial from affected women must be available; and (4) a 10% chance of recombination between the polymorphism and the breast cancer gene provides a 10% margin of error in predicting risk for any individual. The p53 gene has been mapped to the short arm of chromosome 17:'8 A germline mutation of this gene has been associated with Li-Fraumeni syndrome, an extremely rare familial cancer syndrome that confers extreme susceptibility to breast cancer, soft tissue sarcomas, brain tumors, bone cancer, leukemia, and adrenocortical carcinoma. The first cancer often appears in childhood or young adulthood, and a second different cancer may develop if the first cancer is survived. In contrast to the cancers just discussed, some of the malignancies associated with this syndrome are not amenable to screening (soft tissue sarcoma, bone, brain) or have no real survival advantage associated with early detection. The ultimate goal of genetic testing is to alter the course of the disease. Eventually this may be achieved through gene therapy or through more traditional chemical approaches based on improved understanding of the biochemical nature of the disease. Soon, we will be faced with the availability of testing for diseases for which we can offer no gene-based cure or immediate advance in traditional therapy. The task of the health care provider will be to help the patient evaluate the risks and benefits of such testing. 9 More precise characterization of risk will allow for more intensive screening and early application of current therapy, as previously discussed for some of the genetic cancers. In such cases, people in whom genetic tests provide a negative result are spared the aggressive screening regimens that they might otherwise have undergone based on estimated risk. Those determined to be at risk might also be advised to minimize exposures to carcinogenic insults, make dietary changes, or take chemopreventive drugs. 5 GENETIC SCREENING AND DISCRIMINATION

There are important nonmedical risks to genetic testing with which health care providers and their patients should be familiar. Significant consequences may exist for the patient in the area of livelihood and insurability. Genetic discrimination has been defined by Natowicz et al l~ as "discrim-

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ination against an individual or against members of that individual's family solely because of real or perceived differences from the "normal" genome in the genetic constitution of that individual." Workplace discrimination includes unfavorable treatment in hiring, promotion, duty assignment, discharge, compensation, and other conditions of employment. H An example from recent history is the US Air Force policy that at one time prohibited heterozygotes with sickle cell anemia from being pilots, based on the belief that these people would have problems at high altitudes. Opponents of this policy maintained there was little evidence to support that belief, and what did exist was anecdotal. 11 As tests for genetic susceptibility to cancer continue to be developed, the possibility of employment discrimination becomes very real. Employers could decide not to hire because of concerns about more frequent absences as a result of illness, lower productivity, or greater health care requirements. Susceptible employees may be prohibited from jobs that entail certain exposures, which is also a decision with public health considerations. People at risk for employment discrimination include affected individuals, presymptomatic or possibly presymptomatic individuals, carriers of recessive disorders, and those at increased risk of multifactorial disease such as cancer. 12 A precedent for this kind of decision making can be noted in the policy of some companies not to hire smokers because of higher health care costs. 12 As 47% of health care costs to companies are for dependents, ~2 even the heterozygote carrier of a genetic disease is at risk for such discrimination. In one survey of people with genetic conditions, respondents with Charcot-Marie-Tooth disease (hereditary sensorimotor neuropathy) were refused employment despite having mild forms of a nonfatal disease. An unaffected heterozygote (carrier) for Gaucher disease reported being denied a government job on that basis. 11 Current legal protection is untested for cases of genetic discrimination. ~ Some authors believe that employment discrimination on the basis of genetics will be contestable under the Americans with Disabilities Act (ADA). ~1"12 The ADA applies to private sector employers as well as to state and local governments. It is already in effect for companies with more than 24 employees and will take effect in July 1994 for companies with more

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than 14 employees. Employees of the federal government are covered by comparable provisions in The Rehabilitation Act of 1973. The ADA defines a physical or mental impairment as one that substantially limits one or more of an individual's major life activities (including working), having a record of such an impairment, or being regarded as impaired (although not impaired). The act requires "reasonable accommodation" to a disability from employers. Under the provisions of the ADA, pre-employment medical examinations and questionnaires are now illegal. However, employers may require an "employment entrance examination" after the job is offered. Current debate centers on whether these exams must be restricted to job-related activities (such as climbing stairs or lifting). ~'~2 The burden of proving discrimination, as in all antidiscrimination laws, is on the applicant or employee. Insurance discrimination based on genetics already happens in significant numbers and will probably be the major immediate risk for people who undergo testing for genetic susceptibility to cancer. A preliminary survey of such cases performed by Natowicz et al 1~ shows several instances of such discrimination. Several respondents with genetic c o n d i t i o n s that were successfully treated before the appearance of symptoms, such as hemochromatosis or phenylketonuria, were denied health insurance coverage or were excluded from their companies' plans. Similarly, those with mild forms of genetic diseases for which there is a great range of severity, such as Charcot-Marie-Tooth disease, were refused life, auto, or health insurance. Others at risk for insurance discrimination include those who may be affected in the future by an untreatable fatal condition such as Huntington disease, those with a genetic factor that increases the probability of a disease such as cancer, those with increased susceptibility to an environmental exposure that would not affect someone with a "normal" genotype (such as G6PD deficiency or malignant hyperthermia), heterozygotes who are carders for an X-linked or recessive condition such as cystic fibrosis, persons with a genetic polymorphism not known to cause disease, and immediate relatives of someone with a known or presumed genetic disease. ~1 The ADA provides that employers may not deny

HUMAN GENOME PROJECT'S ETHICAL IMPLICATIONS

health insurance coverage completely based on diagnosis or disability but may place limitations on reimbursements for particular procedures to the extent permitted by state insurance law. The ADA does not refer to insurance other than health insurance. Although forty-one states prohibit unfair discrimination by insurers, this is defined as discrimination not justified by actual risk. Only a small but increasing number of states currently have laws that specifically restrict use of genetic information by employers or insurers. These states include Maryland, North Carolina, New Jersey, and California, lO Health information can find its way into the hands of insurers and employers in many ways. Requests for health records must be scrutinized to ensure that only the information released by the patient is included. Patients need to be educated about what their record contains, and the possible consequences of its release. Additional issues regarding ownership of information are problematic in cases of genetic diseases. The fights of other family members to information that may have a direct effect on their health care are unclear. Consentability also is an issue: Do parents have the fight to test their children for diseases that will not manifest until adulthood, or should that decision be deferred until the child can weigh the risks and benefits and decide? PSYCHOSOCIAL EFFECTS OF GENETIC SCREENING

Diagnosis of a genetic susceptibility has possible effects on self-image, psychological adjustment, and role in the family. 9 There is not an abundance of studies examining the psychological effect of being diagnosed with a familial cancer. Kellock's study on FAP described guilt associated with the hereditary nature of the disease. ~3 Miller et a114 surveyed FAP patients at least 1 year postcolectomy with ileorectal anastomosis. Although initial responses to the diagnosis included the belief that life would never be the same, anger, anxiety, and fear of death, 82% of respondents reported their current health as being excellent or good. Younger respondents and those more recently diagnosed were more likely to report negative attitudes about disease. Accuracy of the respondents' knowledge about the disease was improved by having more than one source of in-

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formation: information from a physician and information from an affected parent. Possession of more accurate information was associated with greater well-being. Accurate and complete information before genetic testing is important to ensure the person's understanding of the limits of the test and possible consequences of testing, including its effect on employment, insurance, and emotional adjustment. The Columbia University program, which offers testing for Huntington disease, requires participants to have a minimum of six counseling sessions before receiving test results and three sessions after receiving them. Each testee must bring a support person. Results are always discussed face-to-face whether positive, negative, or noninformative. Those unable to give informed consent (children, adolescents, and those with psychiatric disabilities that preclude consent) are not tested. 15 THE ETHICAL DILEMMA

Decisions about prenatal genetic testing require particularly sensitive counseling. The skills of trained genetic counselors and genetic consult services are used more often in this setting, which has traditionally dealt with genetic diseases with effects manifested in early childhood. The rapidly increasing number of tests for genetic susceptibilities to diseases that present in adulthood and are multifactorial in origin poses new problems. Hymie Gordon, MD, Professor Emeritus of Medical Genetics at Mayo Clinic, made the following observation: I foresee a much greater ethical problem for the future-one that boggles my mind! In the foreseeable f u t u r e . . , it will become possible to examine an individual's entire genetic endowment, possibly even soon after conception, and determine whether the individual is destined to have glaucoma, schizophrenia, hypertension, coronary artery disease, some kind of cancer, myopia, or blond hair and blue eyes . . . . Are parents going to decide they don't want a baby because she might have breast cancer, or because she might eventually have glaucoma? Every one of us carries genes that make us susceptible to all kinds of diseases; there can never be such a thing as a perfect human genetic code. ~6

The "myth of genomic perfection" has affected everything from adoption policy to insurance policy. ~0 Physician attitudes, too, are not immune. A woman with distal arthrograposis, an autosomal dominant condition involving deformities of the

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hands and feet, described her experience of prenatal care received at a university hospital: There was a big difference between talking to a geneticist and a doctor. We didn't want a lot of testing. The doctors really pressured for abortion. I felt like they were looking at me like I shouldn't be alive. [They were] very cold, like they were saying "if it's not perfect, get rid of it", like they thought I wasn't a whole person. C o n v e r s e l y , health care providers m a y face medicolegal problems for not testing low-risk patients. L y n n Fleischer, who has a doctoral degree in genetics and is a lawyer, predicted an increase in cases in which physicians are charged with failure to inform patients of prenatal and carrier screening tests. Dr. Fleischer cited a " w r o n g f u l b i r t h " case decided against a physician who did not counsel a non-Jewish couple about the availability of a test for Tay-Sachs disease.17

The possible ethical, social, and legal consequences of the H u m a n G e n o m e Project are attracting public and media attention. R e n a Pederson, ~s columnist of the Dallas Morning News, stated, " I m a g i n e the moral d i l e m m a facing researchers who m a y have it within their power to tell patients to begin treatment early to lessen the chances o f fatal disease only to have those same patients unable to afford the needed treatment for lack o f insurance c o v e r a g e . " Several books about the Hum a n G e n o m e Project written in lay language have been published. 19-21 The concerns raised by the H u m a n G e n o m e Project are of such magnitude that the project set a new precedent by devoting 5% of its funds for the consideration of such matters. The results of these deliberations may well have effects as far-reaching as the results of the Project itself.

REFERENCES

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12. Rothstein MA: The genome project as public policy. Bull NY Acad Med 68:144-150, 1992 13. Kellock G: The disease of familial polyposis: Its impact on families. J Enterostom Ther 8:12-13, 1981 14. Miller HH, Bauman LJ, Friedman DR, et al: Psychosocial adjustment of familial polyposis patients and participation in a chemoprevention trial. Int J Psychiatry Med 16:211-231, 1986 15. Wexler NS: Disease gene identification: Ethical considerations. Hosp Pract 26:113-117, 1991 16. Gordon H: Examining the past, present, and future of clinical genetics. Minn Med 75:11-14, 1992 17. Merz B: Ignorance of genetics may lead more doctors to court. Am Med News 34:18-23, 1991 18. Pederson R: Gene research: Is a brave new world on the horizon? Dallas Morning News, October 10, 1991 19. Davis J: Mapping the Code: The Human Genome Project and the Choices of Modern Science. New York, NY, Wiley, 1991 20. Wingerson L: Mapping Our Genes: The Genome Project and the Future of Medicine. New York, NY, Dutton (Penguin), 1990 21. Bishop JE, Waldholz M: Genome: The Story of the Most Astonishing Scientific Adventure of Our Time-The Attempt to Map All of the Genes in the Human Body. New York, NY, Simon & Schuster, 1990