genetic testing

UNDERSTANDING CLINICAL TRIALS 0889-8588/00 $15.00 + .OO

GENETIC TESTING

Gloria M. Petersen, PhD

The growing understanding of the molecular basis of carcinogenesis has revolutionized the field of cancer geneti~s.5~ The discovery of genes that, when somatically altered, are involved in tumor development and in the progression of a variety of cancers has led to entirely new avenues of research to identify molecular targets for therapeutic interventions and management of cancer patients.27 The process of gene discovery has been greatly enhanced by the study of families with hereditary cancer to identify and characterize the molecular basis of susceptibility to cancer.14 This research strategy has resulted in the identification of doz- ens of cancer genes associated with a variety of hereditary cancer syndromes.34 Table 1 summarizes some of the better known syndromes for which genetic testing may improve cancer risk management of patients and their families.

The results of subsequent studies that link mutational and molecular data with clinical phenotypes among patients and families have been even more intriguing. For example, mutation in the APC gene was found to be the genetic basis for the autosomal dominant colorectal cancer syndrome, familial adenomatous polyposis (FAP). It was subsequently discovered that Gardner ' s syndrome (in which additional extracolonic manifestations occur, such as osteomas and desmoid tumors) was caused by mutations in the same gene and could be clinically categorized with FAP on molecular On the other hand, in some patients Tur- cot's syndrome, once thought to be an autosomal recessive condition

This manuscript was supported in part by NIH Grant HG01197 and a Richard Gelb Fellowship in Cancer Prevention.

From the Department of Health Sciences Research, Section of Clinical Epidemiology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota

HEMATOLOGY / ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 14 NUMBER 4 AUGUST 2000 939

Tabl

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GENETIC TESTING 941

featuring colon tumors and brain tumors,5* has been found to result from mutations in the APC gene (which cause FAP), but in other patients Turcot’s syndrome is caused by mismatch repair genes associated with autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.20 Thus, molecular genetic testing can enhance clinical diagnoses. It has also been learned that, depending on the location of a mutation within a gene, there may be variation in phenotype severity. The location of the mutation in the APC gene may cause attenuated polyposis or dense p0lyposis.4~, 48 A gene can give rise to different syndromes altogether. For example, multiple endocrine neoplasia type 2A and type 2B, familial medullary thyroid cancer, and Hirsch- sprung’s disease are all caused by mutations involving different regions of the RET gene?, 13, 33, 44 The ability of molecular genetic testing to distinguish among various forms of inherited cancer will prove valuable as genetic knowledge and technology are incorporated into clinical practice.

RELEVANCE OF GENETIC TESTING TO CLINICAL TRIALS

Genetics research carries many implications for future clinical trials addressing issues of therapy, early detection, and prevention. Specifi- cally, the identification of cancer gene mutation carriers has led to the discovery of potential variation in prognosis among such individuals. This variation indicates a concomitant need to tailor therapies for genetic subgroups of patients. For example, women who carry mutations in the genes associated with hereditary breast and ovarian cancer syndrome, BRCAl or BRCA2, may be at increased risk for breast cancer-related events following breast conservation surgery, possibly mandating management strategies different than those used for women without such mutati0ns.4~ Colorectal cancer patients whose tumors manifest DNA microsatellite instability and patients with the mismatch repair gene mutations associated with HNPCC syndrome may have improved survival, regardless of ~tage.2~. 54 Moreover, patients with HNPCC are at increased risk for multiple or metachronous colorectal malignancies, and some have suggested that subtotal colectomy rather than segmental resection may be mandated,32 although at this time the evidence is based on clinical experience Because it may be clinically useful to identify genetically high-risk individuals, cancer genetic testing will become an important consideration in designing observational studies and some clinical trials.

CANCER GENETICS IN THE CLINIC

The development of clinical cancer genetics services has been a natural evolution of the increasing clinical knowledge base and the

942 PETFlRSEN

recognition of the care which must be exercised in providing this information to patients.z37 Certain gene tests (APC, RET, RB1, VHL) may now be considered part of the standard management to idenhfy and intervene in high-risk individuals in families with the respective hereditary cancer syndromes whereas the medical benefit of other gene tests (hMSH2, hMLH1, hPMS1, hPMS2, BRCA1, BRCA2, and p53) is presumed but not established.*

The gene test outcome for an individual patient or family member can lead to more informed and directed recommendations for preventive interventions. For example, before the availability of genetic testing, conventional cancer-risk assessment for at-risk persons often consisted of family history evaluation, followed by recommendations for screening that were based largely on expert opinion. Now, with a larger information base and the availability of genetic testing services, information gleaned from family history evaluation can be used more effectively to help make a diagnosis and to speufy more precisely clinical management of cancer patients. Equally important, interventions (intensive screening, surge and possibly chemoprevention) can be tailored for

who test negative may perhaps forgo su Genetic testing for cancer risk also carries psychosocial implications

that should be communicated through careful genetic counseling to both patients and family members who are considering cancer gene tests. Genetic counseling will entail directive counseling toward cancer prevention where indicated, but it will also entail communication about complex issues related to heredity, genetic test performance, probabilities, and uncertainty of outcome.

Cancer gene testing involves a variety of issues, including those related to clinical applications (gene test algorithms, follow-up management), genetic counseling (informed consent, psychologic impact, family relationships), social, legal, and ethical considerations (privacy of gene test results, genetic discrimination). In this nascent period of gene testing for cancer risk, few of these issues are fully resolved, and many continue to arise. This article reviews the elements of the genetic testing process and summarizes current recommendations for genetic risk assessment and the use of genetic testing.

a at-risk persons w ?7 o may test positive for ene mutations; at-risk persons interventions.

INDICATIONS FOR CANCER GENE TESTS

At this time, cancer gene tests have two primary clinical applications. When affected individuals are tested, gene tests may be used for molecular diagnosis of an inherited cancer syndrome. When asymptomatic persons are tested, gene tests may be used to idenm whether they are at inmased risk because they carry a known predisposing mutation. The appropriate use of gene tests, and particularly determining who should be tested, is relatively straightforward in families with clearcut hereditary cancer syndromes. Further characterization of cancer gene

GENETIC TESTING 943

loci may indicate that gene tests can be used in familial cancers (i.e., cancers that may be caused by mutations that are associated with a lower lifetime risk of cancer than hereditary cancers and with pedigrees that do not fit known criteria for hereditary syndromes), or in screening specific populations in which cancer susceptibility genes occur fre- q ~ e n t l y . ~ ~

Testing Affected Individuals

A patient with cancer might be offered gene testing to confirm or rule out a suspected inherited syndrome. In this case, there may be indications from family history or from clustering of specific tumors in family members suggestive of a hereditary syndrome (such as leukemia, soft tissue sarcoma, brain tumors, and breast cancer in Li-Fraumeni

Table 1 lists some of the tumor types that cluster in families with known cancer syndromes. Gene tests may also be offered to patients with apparently sporadic cancer if the cancer occurs at an unusu- ally young age or if the patient has other indications that suggest a hereditary syndrome. For example, FAP might be suspected in a patient who has multiple colonic adenomas, congenital hypertrophy of the retinal pigment epithelium, and desmoid tumor, but no family history of colon polyps or cancer. APC gene testing is indicated as a diagnostic test, because this patient could have a de novo mutation in the APC gene.39 If the APC gene test is positive, this patient can be assumed to have FAP, and the patient’s children have a 50% risk of inheriting the mutation.

Because genetic heterogeneity is seen in some hereditary cancer phenotypes, gene tests may be used help to identify the specific locus that is involved. For example, patients from families in which hereditary breast cancer is suspected may need to be tested for at least two genes, BRCAI and BRCA2, because both genes may produce similar family histories.l6< 51

Testing At-Risk Individuals

Asymptomatic at-risk persons from families known to carry a hereditary cancer syndrome may benefit from gene testing. When a mutation in a cancer gene is known to be segregating in the family, at-risk persons who test negative for the mutation may be relieved of years of surveillance, whereas persons who test positive for the mutation may approach the screening regimen with greater willingness to adhere to the recommendations.28, 39

Gene tests of at-risk persons are more problematic when a mutation is not known to segregate in a cancer family or if the diagnosis of a cancer syndrome is less clearcut. Often, there may not be a living family member with cancer who can undergo gene testing to identify the mutation. In such instances a negative gene test result in an at-risk

944 PETERSEN

person is not a true negative result that places him or her at the general population risk for that cancer. Rather this person has an inconclusive or uninformative negative test result that does not rule out other cancer gene loci or even other mutations in the tested locus that the particular gene test was not able to detect. A person receiving an inconclusive test result should continue to maintain a cancer surveillance regimen as though no gene test was ever done.

It has been found that certain types of mutations in cancer genes occur with higher frequency in certain populations, and genetic screening tests may be developed that can be targeted to specific populations. For example, two mutations in BRCAI, 185delAG and 5382insC, and a mutation in BRCA2,6174delT, occur frequently enough in the Ashkenazi Jewish population that genetic screening for these mutations directed to Ashkenazi Jewish persons may be

CANCERGENETESTS

One of the most consistent patterns to emerge from genetic studies of inherited cancer syndromes is that there are many mutations in cancer genes, and many families have unique mutations. Thus, testing laboratories have had to develop a variety of different strategies for detecting mutations in patients or diagnosing at-risk individuals in families with inherited cancer syndrome. These tests include linkage analysis, single-stranded conformational polymorphism analysis, protein truncation tests, direct DNA sequencing, and allele-specific oligonucleo- tide assays. The relative merits and drawbacks of various means of detecting mutation have been reviewed el~ewhere,'~, 21 and different laboratories use different strategies for gene testing.

Because current mutation analysis technology is relatively sophisti- cated, understanding and interpreting the potential implications of gene test results is not always simple for the clinician. When a clearcut test result is obtained, either because a disease-predisposing mutation is detected (positive gene test), or a mutation is not detected in an at-risk person from a fainily in which a known mutation is segregating (true negative gene test), the subsequent counseling and management options are more apparent. Inconclusive or uninformative negative gene tests will occur when no mutation is detected in a cancer family but, because of the limitations of the testing method, a mutation in the tested locus (or elsewhere) cannot be ruled out. At-risk members in these families should not reduce their vigdance in cancer screening.

The Task Force on Genetic Testing of the National Institutes of Health and Department of Energy (NIH-DOE) Working Group of the Ethical, Legal, and Social Implications of Human Genome Research has set forth recommendations on gene testing relative to gene test validation and testing laboratory quality control,23 and regulatory or le 'slative

for this attention to cancer gene tests are the arguments that the complex- policies for oversight of this technology may be developed.& Ti? e basis

GENETIC TESTING 945

ities of assessment and interpretation make gene tests different from other clinical tests and that gene tests require more intake information. Experts propose that health care providers become educated on these issues so that patients can be appropriately prepared for gene testing.

Tissue Sources for Clinical Gene Testing

The most common tissue source for gene testing is leukocyte DNA; a simple blood sample is often all that is required to perform a gene test. DNA can also be obtained from paraffin-embedded tissue blocks obtained at surgery if an affected relative is deceased or obtaining a blood sample is not feasible.

Specific tumor DNA studies may also yield information to aid in the diagnosis of inherited susceptibility to cancer. In HNPCC, a special tumor analysis can identify microsatellite instability, which occurs in the majority of such patients, but a minority of sporadic colorectal cancer patients? lo In this analysis, DNA from both normal tissue and tumor tissue are analyzed by highly polymorphic microsatellite DNA markers, and their banding patterns are compared. Allele alterations (band shifts) seen between tumor and normal DNA, or decreased immunohistochemical expression, suggest that the patient may have an impaired ability to repair DNA (mismatch repair). In some cases this indication serves as an indirect assessment of forms of HNPCC that are caused by mutations in mismatch repair genes (hMSH2, hMLH2, hPMS1, and hPMS2).

PSYCHOSOCIAL AND ETHICAL ISSUES IN CANCER GENE TESTING

Although widespread genetic cancer screening of the general population will not occur soon, genetic testing is being targeted to selected cancer patients and families. From surveys of such persons, it seems that there is great interest in receiving gene testing to assess cancer risk.29, 41 The perception of cancer risk is increased among persons with a positive family history of cancer, and these individuals may be more likely to choose this option for learning more about their cancer risk. In both research and clinical settings, however, when patients are actually presented with the option of gene testing, the percentage of patients who elect to be tested is lower than the percentage of patients who express an interest in being tested in surveys. This discrepancy results from a variety of causes, including the patient’s coping ability, the value of the gene test information to the individual, and economic considerations.lz> 24

Psychologic Issues

The psychologic consequences following disclosure of gene test results, and particularly after positive (mutation carrier) tests, include

946 PJZERSEN

distress, depression, and anxiety-associated decision makingm For example, at-risk women who chose prophylactic mastectomy were more anx- ious and had higher levels of concern about cancer than women who instead chose continued screening or a chemoprevention trial." In a study of 42 children at risk for FAP and their parents, Codori et all' did not observe any major increase in distress or behavioral problems in the children who tested positive. Patients who receive negative (noncarrier) test results have favorable psychologic reactions, because the uncertainty has been removed, they are better able to prepare for the future, and they do not have to worry about passing a mutation on to their children.m There is a potential risk of survivor guilt, in which persons who test negative experience distress because they were spared whereas others in the family may have cancer.

Risk of Genetic Discrimination

Persons at risk for cancer face other risks in the form of genetic discrimination. They may encounter problems finding or retaining em- ployment4 or obtaining permission for adoptions. Insurance companies may use genetic information, much as they use any other medical information, to underwrite an insurance policy. Insurance companies may deny insurance to persons they consider to be at too great a risk for an illness or to persons with pre-existing conditions?, 26 Discrimina- tion can occur against the asymptomatic mutation carriers, who can lose their insurance after undertaking preventive care?, 26 They may have trouble obtaining coverage, or insurance problems can arise when people alter existing policies because of relocations or job changes. Although the United States Equal Employment Opportunity Commission stated in its 1995 compliance manual that healthy people carrying abnormal genes will be protected against employment discrimination by the Americans with Disabilities Act, protection from loss of insurance awaits additional legislation.

Privacy of Genetic Information

Genetic information should be considered confidential, and health professionals and laboratories must exercise all means to prevent unauthorized disclosure of gene test results to third parties. In practice, it is recommended that results be released only to persons whom the patient designated or subsequently requested in writing, and care should be taken to minimize the likelihood that results will become available to unauthorized persons or organizations.23 Garber and Patenaudel* point out that physicians may breach confidentiality unintentionally by plac- ing information in medical charts that may be reviewed by insurers or other third parties. The dilemma is omitting this information may compromise the patient's future medical care, but including it may

GENETIC TESTING 947

compromise the ability of the patient or family members to obtain health, life, or disability insurance (and therefore coverage for preventive screening tests or procedures).

Another crucial issue is the revelation of gene test results to family members. The optimal algorithm for gene testing at-risk persons is first to test a family member who is affected with cancer. This patient must be willing to have the resulting genetic information shared with relatives. It is an important principle of gene testing that health care providers have an obligation to the person being tested not to inform other family members without the permission of the person tested.23 Sometimes family members may refuse to have their gene test result shared. There are circumstances in which certain individuals may not want their test results known, but by virtue of the pedigree structure this information will become known (i.e., an identical twin of a gene-positive patient). The resolution of these issues may not always be easy and may call for careful planning and thorough genetic counseling with the family members involved, preferably before gene test results are available.

PROCESSOFCANCERRISKASSESSMENTAND GENETIC COUNSELING

Who Should Be Referred?

Persons who may be considered for genetic risk assessment and possibly for gene testing include patients and family members of patients with a diagnosis of a known hereditary cancer syndrome, members of families with a known cancer gene mutation, patients with multiple primary cancers, patients with a positive family history of cancer, patients with young onset of cancer (generally under age 50), or persons of Ashkenazi Jewish heritage.

Evaluating Family History

A detailed three-generational family history should be elicited, including information on age, disease, and cancer history, and vital status of all first- and second-degree relatives and age and cause of death of deceased relatives. Similar information about relevant third-degree relatives should be obtained, as should ethnicity or nationality of ances- tors. Follow-up confirmation of cancer diagnoses in family members will be valuable and should be requested, when possible. Evaluation of the pedigree will assess the types and patterns of cancer, and cancer-risk or mutation-carrier probability models may be applied*7, 38 to develop a management plan. Genetic testing may not necessarily be the best option for some patients or families. If genetic testing is performed, follow-up plans for all potential test outcomes should be considered. For example, if a specific causal gene mutation cannot be identified, genetic testing of

at-risk family members should not be pursued. If a specific causal gene mutation is identified, the diagnosis of the corresponding hereditary cancer syndrome can be confirmed. In this instance, genetic counseling and predictive gene testing may be offered to at-risk family members who may wish to have this test done.

An at-risk person who tests positive for the gene will be encouraged to adhere to preventive screening recommendations specific to the hereditary syndrome and counseled regarding other options, such as prophylactic surgery or chemoprevention, if applicable. For example, recommendations have been developed for hereditary breast and ovarian cancer and hereditary nonpolyposis colon c a n ~ e r . ~ , ~ If an at-risk person from a family in which the mutation in the cancer gene is known to segregate tests negative for the mutation, that person can follow cancer screening guidelines for the general population.

Genetic Counseling Issues

Genetic counseling should accompany genetic testing and has been shown to reduce adverse psychologic reactions.', 31 Before testing, counseling will identdy and help alleviate potentially serious implications for the entire family, including persons not tested. For example, all the offspring of a person with a gene for an autosomal dominant form of cancer have a 50% risk of inheriting the mutation. AU the grandchildren of that person are at 25% risk of inheriting the mutation. When an affected person tests positive for a hereditary form of cancer the entire family may suddenly become aware of an suddenly increased risk for cancer. An identical twin cannot be tested without, in effect, automatically informing the other twin, whether or not the untested person wants the information. Similarly, a person at 25% risk for cancer (i.e., a person with an affected grandparent and a healthy at-risk parent) who tests positive for the mutation automatically gives a genetic diagnosis to the unaffected parent.

The process of genetic counseling at the initial (pretesting) session includes

1. Educating the family about the clinical and management aspects of hereditary cancer. The counseling should entail the risks of cancer within the syndrome, the consequences of receiving gene- positive or gene-negative test results, and the evidence regarding the efficacy of clinical cancer screening for each possible test outcome.

2. Exploration of the issues related to the family history and experi- ences with cancer. These experience can be multigenerational and can include personal involvement with relatives who have died from cancer or who had oncologic or surgical interventions. Family relationships can be profoundly marked by issues such as @t and blame, and personal and familial identity may be

GENETIC TESTING 949

strongly linked with cancer status. Other issues include the denial of disease risk or stigmatization of cancer within the family, and the acceptability, convenience, or affordability of screening regimens. Thus, genetic testing is imbued with meaning for certain patients far beyond its ostensible function as a simple deter- miner of genetic status. The at-risk patient may have preformed, well-entrenched conceptions of what having cancer entails, and family relationships and identity may be strongly linked with disease or gene status. Understanding the patient's perspective is crucial to help the patient adjust to genetic test results.

3. Exploration of the perception of risk and its meaning and the anticipated meaning of any test results. With parents of at-risk minor children, time should also be devoted to discussing how and when the test results and risk information will be communicated to children. In certain countries, employability or loss of insurability is a risk, although the magnitude of this risk is at present unknown.

Informed Consent for Gene Testing

The decision to move forward with the gene test should be freely made by the at-risk person after carefully considering the consequences of genetic testing. It is strongly recommended that a consent form that outlines the meaning of test results and the consequences of the gene test be used. If patients are to make fully informed decisions about gene testing, the informed consent process must include discussions of several complex issues.This process can require at least an hour of counseling time. The genetic counseling process that should accompany gene testing should incorporate the basic elements of informed consent, as shown in the following list.2 42

1. Information on the specific test being performed 2. Implications of a positive and a negative result 3. Possibility that the test will not be informative 4. Options for risk estimation without genetic testing 5. Risk of passing a mutation to children 6. Technical accuracy of the test 7. Fees involved in testing and counseling 8. Risks of psychologic distress 9. Risks of insurance or employer discrimination

10. Confidentiality issues 11. Options and limitations of medical surveillance and screening

following testing

Disclosure and Postdisclosure Counseling

Disclosure of gene test results, which (depending on the laboratory) can occur 2 weeks to 2 months later, provides another opportunity to

950 PETERSEN

meet with the at-risk family member, to explore the meaning of the test, and to discuss in a more substantial way the likely follow-up regimen and cancer risks to future offspring. There may be several such counseling sessions, depending on the patient's needs.

SUMMARY

New research developments in the molecular genetics of cancer have led to the feasibility of cancer genetic testing. At present, genetic test results can better inform individuals at risk about appropriately tailored strategies for cancer screening and prevention. In the future, more persons will be eligible for genetic evaluation; in particular, if it is shown that patients with cancer who are carriers of germline mutations respond differently to treatments, genetic testing may be warranted. Consideration needs to be given to the appropriate delivery of genetic risk assessment and testing. There is a great potential for misinterpreta- tion of gene test results and for adverse psychosocial consequences for patients. Genetic counseling is an important component in cancer risk assessment and management, particularly in helping persons at risk understand the implications of gene test results in the context of their experience with cancer and surveillance.

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GENETIC TESTING 951

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Address reprint requests to Gloria M. Petersen, PhD

Mayo Clinic 200 First Street SW

Rochester, MN 55905

e-mail: [email protected]

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