Significance of the Terms Mutation and Carrier
Assumptions Concerning the Identification of People With an Increased Susceptibility to Cancer
Evaluation of Evidence
Evidence Related to the Clinical Value of Genetic Tests and Family History Information
        Analytic validity
        Clinical validity
        Clinical utility
Genetic Counseling
Quality of Evidence
Study Populations
Evidence Related to Screening
Evidence Related to Cancer Prevention

Knowledge about cancer genetics is rapidly expanding, with implications for all aspects of cancer management, including prevention, screening, and treatment. PDQ cancer genetics summaries provide information on the genetics of specific cancers, inherited cancer syndromes, and the ethical, legal, social, and psychological implications of cancer genetics knowledge. Sections on the genetics of specific cancers include information on the prevalence and characteristics of cancer-predisposing mutations, the risk implications of a family history of cancer, known modifiers of genetic risk, opportunities for genetic testing, outcomes of genetic counseling and testing, and interventions available for people with increased cancer risk resulting from an inherited predisposition.

A mutation is a change in the usual DNA sequence of a particular gene. Mutations can have harmful, beneficial or neutral effects on health, and may be inherited as autosomal dominant, autosomal recessive, or X-linked traits. Mutations that cause serious disability early in life are usually rare in the population, because of their adverse effect on life expectancy and reproduction. However, if the mutation is autosomal recessive, that is, if the health effect of the mutation is caused only when two copies of the mutation are inherited, carriers (healthy people carrying one copy of the mutation) may be relatively common. “Common” in this context generally refers to a prevalence of 1% or more. Mutations that cause health effects in middle and old age, including several mutations known to cause a predisposition to cancer, may also be relatively common. Many cancer-predisposing mutations are autosomal dominant, that is, the cancer susceptibility occurs when only one copy of the mutation is inherited. For autosomal dominant conditions, the term carrier is often used in a different way, to denote people who have inherited the genetic predisposition conferred by the mutation. Detailed information on known cancer-predisposing mutations is reviewed in relevant PDQ summaries on genetics of specific cancers.

Genetic information, including information from family history and from DNA-based testing, provides a means to identify people who have an increased risk of cancer. Family history often identifies people with a moderately increased risk of cancer, and in some cases may be an indicator of the presence of polymorphisms that influence cancer susceptibility, through such mechanisms as changes in the rate of metabolism of agents that predispose to cancer or catabolism of carcinogens, or effects on DNA repair or regulation of cell division. Less often, family history indicates the presence of an inherited cancer predisposition conferring a relatively high lifetime risk of cancer. In some cases, DNA-based testing can be used to confirm a specific mutation as the cause of the inherited risk, and to determine whether family members have inherited the mutation.

Identifying a person with an increased risk of cancer can reduce the occurrence of cancer through clinical management strategies (e.g., tamoxifen for breast cancer, colonoscopy for colon cancer) or improve that person’s health outcome or quality of life through intrinsic benefits of the information itself (e.g., no genetic predisposition). Intrinsic benefits may include better ability to plan for the future (having children, career, retirement or other decisions) with improved knowledge about cancer risk. Methods of genetic risk assessment include assessment of personal and family history of disease and genetic testing; the latter is generally undertaken only when family history of disease or other clinical characteristics, such as early onset of cancer, indicate a substantial likelihood of an inherited predisposition to cancer.

Genetic testing may also be sought by people affected with cancer, both newly diagnosed individuals and survivors of earlier cancers. Testing may be desired to define personal cancer etiology, to clarify risk to offspring, to define the appropriateness of particular surveillance approaches, or to aid in decision-making about risk-reducing prophylactic surgery.[1] While there are effective interventions specific for some cancer genetic syndromes (e.g., multiple endocrine neoplasia type 2A [MEN 2A], familial adenomatous polyposis [FAP], retinoblastoma [RB]), genetic testing is still being integrated into the management of patients with hereditary forms of common cancers (e.g., breast cancer).[2] Some patients and physicians may wish to include genetic risk status as a factor in consideration of treatment options (refer to the Interventions section in the PDQ summary on Genetics of Breast and Ovarian Cancer for more information).

A genetic assessment is likely to aid clinical decision-making only when management is based on genetic information (e.g., when the clinical interventions being considered would be offered to genetically susceptible people but not to those of average risk, or when interventions that are effective in people of average risk are ineffective in those with genetic susceptibility). Intrinsic benefits of genetic information, for example, improvement in quality of life as a result of knowledge about genetic susceptibility, may be accompanied by potential personal and social risks as well (e.g., reduced self-worth; guilt; family disruption; stigmatization; or loss of health, disability, or life insurance). PDQ summaries on cancer genetics include available evidence addressing these points. Genetic information may sometimes provide a direct health benefit by demonstrating the lack of a known inherited cancer susceptibility. For example, if a family is known to carry a cancer-predisposing mutation, a family member may experience reduced worry and lower health care costs if his/her genetic test indicates that he/she does not carry the mutation. The family member may be able to forego certain medical tests, such as early use of colonoscopy for persons at high risk of a hereditary nonpolyposis colon cancer (HNPCC) mutation.

Creating evidence-based summaries in cancer genetics is challenging because the rapid evolution of new information often results in evidence that is incomplete or of limited quality. In addition, established methods for evaluating the quality of the evidence are available for some but not all aspects of cancer genetics. Varying levels of evidence are available for different topics, and PDQ summaries are subject to modification as new evidence becomes available. As in other aspects of medicine, testing and treatment decisions must be based on information that sometimes falls short of the optimal level of evidence, i.e., data from randomized trials.

In assessing a genetic test (or other method of genetic assessment, including family history), the analytic validity, clinical validity and clinical utility of the test need to be considered.[3]

Analytic validity refers to how well the genetic assessment performs in measuring the property or characteristic it is intended to measure. In the case of family history, analytic validity refers to the accuracy of the family history information. In the case of a test for a specific mutation, analytic validity refers to the accuracy of a genetic test in identifying the presence or absence of the mutation. Analytic validity of a genetic test is affected by the technical accuracy and reliability of the testing procedure, and also by the quality of the laboratory processes (including specimen handling).

The evaluation of analytic validity is complex for some genetic tests. A panel test, for example, tests for the presence of a particular set of mutations (e.g., the known deleterious mutations in the BRCA1 gene), and the analytic validity of the different components of the test may vary. Some genetic tests involve the evaluation of the DNA sequence of portions of a gene, to determine whether any mutations are present. The sensitivity and specificity of these sequencing tests may vary with the laboratory techniques employed, the proportion of the gene tested, and the structural nature of the mutations present in the gene.

Clinical validity refers to the predictive value of a test for a given clinical outcome (e.g., the likelihood that cancer will develop in someone with a positive test), and is in large measure determined by the sensitivity and specificity with which a test identifies people with a defined clinical condition. Sensitivity of a test refers to the proportion of persons who test positive from among those with a clinical condition; specificity refers to the proportion of persons who test negative from among those without the clinical condition. In the case of genetic susceptibility to cancer, clinical validity can be thought of at two levels: (1) Does a positive test identify a person as having an increased risk of cancer? (2) If so, how high is the cancer risk associated with a positive test? Thus, the clinical validity of a genetic test is the likelihood that cancer will develop in someone with a positive test result. This likelihood is affected not only by the presence of the gene itself, but also by any modifying factors that affect the penetrance of the mutation, for example, the carrier’s environment or behaviors (or perhaps by the presence or absence of mutations in other genes). For this reason, the clinical validity of a genetic test for a specific mutation may vary in different populations. If the cancer risk associated with a given mutation is unknown or variable, a test for the mutation will have uncertain clinical validity. A summary of definitions of concepts relevant to understanding clinical validity and other aspects of cancer genetics testing has been published.[4]

The test should be evaluated in the population in which the test will be used. Evidence that mutations in a particular gene result in a cancer predisposition often derives initially from linkage studies that use samples of families meeting stringent criteria for autosomal dominant inheritance of cancer risk. The demonstration of strong linkage of cancer to a pattern of autosomal dominant inheritance supports a causal molecular mechanism for the inherited cancer predisposition. Once linkage is established, a strong case for association between the genetic trait and disease can be made, even though the families used in the study are not representative of the general population. The genetic trait measured in linkage studies is not always the causal function itself, but may instead be a genetic trait closely linked to it. Additional molecular studies are required to identify the specific gene associated with inherited risk, after linkage studies have determined its chromosomal location.

Linkage studies, however, provide only limited evidence concerning either the range of cancer types associated with a mutation or the magnitude of risk and lifetime probability of cancer conferred by a mutation in less selected populations. In addressing these questions, the best information for clinical decisions comes from naturally occurring populations in which people with all degrees of risk are represented, similar to those in which clinical or public health decisions must be made. Thus, observations about cancer risk in families having multiple members with early breast cancer are applicable only to other families meeting those same clinical criteria. Ideally, the families tested should also have similar exposures to factors that can modify the expression of the gene(s) being studied. The mutation-associated risk in other populations, such as families with less dramatic cancer aggregation, or the general population, can best be assessed by direct study of those populations.

The clinical utility of the test refers to the likelihood that the test will, by prompting an intervention, result in an improved health outcome. The clinical utility of a genetic test is based on the health benefits of the interventions offered to persons with positive test results. Three strategies are available to improve the health outcome of people with a genetic susceptibility to cancer: screening to detect early cancer or precancerous lesions, interventions to reduce the risk of developing cancer, and interventions to improve quality of life. Evaluation of interventions should consider their efficacy (capacity to produce an improved health outcome) and effectiveness (likelihood that the improved outcome will occur, taking into account actual use of the intervention and recommended follow-up). Sometimes genetic information may lead to consideration of changes in the approach to clinical management, based on expert opinion, in the absence of proof of clinical utility.

Genetic counseling has been defined by the American Society of Human Genetics as “a communication process which deals with the human problems associated with the occurrence or risk of occurrence of a genetic disorder in a family. The process involves an attempt by one or more appropriately trained persons to help the individual or family to:

1. comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management;
2. appreciate the way that heredity contributes to the disorder and to the risk of recurrence in specific relatives;
3. understand the alternatives for dealing with the risk of recurrence;
4. choose a course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision; and
5. make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder.”[5]

Central to genetic counseling philosophy and practice are the principles of: voluntary utilization of services, informed decision-making, nondirective and noncoercive counseling when the medical benefits of one course of action are not demonstrably superior to another, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of client confidentiality and privacy. Genetic counseling generally involves some combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity. Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[6-9]

In the 1990s, genetic counseling expanded to include discussion of genetic testing for cancer risk as more genes associated with inherited cancer risk were discovered. Cancer genetic counseling often involves a multidisciplinary team of health professionals who have expertise in this area. The team may include a genetic counselor, genetic advanced practice nurse, medical geneticist, mental health professional, and medical expert such as oncologist, surgeon, or internist. The process of counseling may require a number of visits in order to address the medical, genetic testing, and psychosocial issues. Even when cancer risk counseling is initiated by an individual, inherited cancer risk has implications for the entire family. Because genetic risk affects biological relatives, contact with these relatives is often essential to collect an accurate family and medical history. Cancer genetic counseling may involve several family members, some of whom may have had cancer, and others who have not.

The quality of evidence depends on the appropriateness of the type of study to the question being evaluated and on how well the study is designed and implemented. In evaluating interventions, the strongest evidence is obtained from a well-designed and well-conducted randomized clinical trial. Other questions, particularly those related to the prevalence and clinical validity of genetic information, and emotional and familial outcomes, require well-designed descriptive studies. For some studies, particular elements of study design, such as the nature of the population studied or the duration of observation, may be crucial in assessing the quality of the study.

During early phases of research in a new area, information relevant to the needs of patients and clinicians may come from work at all levels of evidence. These include well-designed quasi-experimental (nonrandomized, controlled single-group, pre/post, cohort, time, or matched case-control series) or nonexperimental studies (case reports, clinical examples, qualitative or narrative studies, or theoretical work). Such research may yield information important to patients and clinicians who must make decisions before full data are available on the risks and benefits of cancer genetic testing. In addition, such work helps to focus future research using rigorous designs with adequate statistical power.

Evidence cited in PDQ cancer genetics summaries is evaluated in terms of its quality. Where relevant, the level of evidence is cited, as described below, or particular strengths or limitations of the evidence are described.

Studies assessing the clinical validity of genetic information from population-based data are not biased by common selection factors. The level of evidence required for informed decision-making about genetic testing, however, depends on the circumstances of testing. Evidence from a sample of high-risk families may be sufficient to provide useful information for testing decisions among people with similar family histories, but it may be insufficient to inform early recommendations for or decisions about testing in the general public. Even among people with similar family histories, however, other contributing genes or different exposures could modify the effect of the mutation for which testing is done. In evaluating evidence, the most important consideration is the relevance of the available data to the patient for whom a genetic assessment is being considered. In summaries addressing the cancer risk associated with mutations and polymorphisms, the study populations used for each risk assessment will be noted, according to the following categories.

1. Population-based.
2. Proxy for population-based. (The study population selected is assumed to be generally representative of the population from which it is drawn. Example: Persons participating in a community-based Tay-Sachs screening program, as a proxy for persons of Jewish descent.)
3. Public recruitment of volunteers, e.g., using a newspaper ad.
4. Sequential case series.
5. Convenience sample.
6. An affected family or several families.

Evidence related to screening is evaluated using the same criteria developed for other PDQ summaries. Refer to the PDQ screening and prevention summaries for more information.

The PDQ Cancer Genetics Editorial Board has adopted the following definitions related to screening:

• Screening is a means of accomplishing early detection of disease in people without symptoms of the disease being sought.



• Detection examinations, tests, or procedures used in screening are usually not diagnostic, but sort out persons suspicious for the presence of cancer from those who are not.



• Diagnosis of disease is made following a work-up, biopsy, or other tests in pursuing symptoms or positive detection procedures.

Five requirements should be met before it is considered appropriate to screen for a medical condition:[10,11]

1. The medical condition being sought causes a substantial burden of suffering, measured both as mortality and the frequency and severity of morbidity and loss of function.
2. A screening test or procedure exists that will detect cancers earlier in their natural history than diagnosis prompted by symptoms, and is acceptable to patients and society in terms of convenience, comfort, risk, and cost.
3. Strong evidence exists that early detection and treatment improve disease outcomes.
4. The harms of screening are known and acceptable.
5. Screening is judged to do more good than harm, considering all benefits and harms it induces as well as the cost, and cost-effectiveness of the screening program.

In order of strength of evidence, the levels are as follows:

1. Evidence obtained from at least one well-designed and conducted randomized controlled trial.
2. Evidence obtained from well-designed and conducted nonrandomized controlled trials.
3. Evidence obtained from well-designed and conducted cohort or case-control analytic studies, preferably from more than one center or research group.
4. Evidence obtained from multiple-time series with or without intervention.
5. Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.

Evidence related to cancer prevention is evaluated using the same criteria developed for other PDQ summaries. Refer to the PDQ screening and prevention summaries for more information.

Prevention is defined as a reduction in the incidence of cancer and, therefore, cancer-related morbidity and mortality. Examples of prevention strategies are a diet high in fiber, fruits and vegetables; regular exercise; smoking cessation; and drugs such as aspirin and folic acid. The strongest evidence is obtained from a well-designed and well-conducted randomized clinical trial with cancer-specific mortality as the end point. It is, however, not always practical to conduct such a trial to address every question in the field of cancer prevention. For each summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the levels are as follows:

1. Evidence obtained from at least one well-designed and conducted randomized controlled trial that has:
   1. A cancer mortality endpoint.
   2. A cancer incidence endpoint.
   3. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
2. Evidence obtained from well-designed and conducted nonrandomized controlled trials that have:
   1. A cancer mortality endpoint.
   2. A cancer incidence endpoint.
   3. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
3. Evidence obtained from well-designed and conducted cohort or case-control studies, preferably from more than one center or research group, that have:
   1. A cancer mortality endpoint.
   2. A cancer incidence endpoint.
   3. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
4. Ecologic (descriptive) studies (e.g., international patterns studies, migration studies) that have:
   1. A cancer mortality endpoint.
   2. A cancer incidence endpoint.
   3. A generally accepted intermediate endpoint (e.g., large adenomatous polyps for studies of colorectal cancer prevention; high-grade squamous intraepithelial lesions of the cervix for studies of cervical cancer prevention).
5. Opinions of respected authorities based on clinical experience or reports of expert committees (e.g., any of the above study designs using nonvalidated surrogate endpoints).

References

1. MacDonald DJ, Choi J, Ferrell B, et al.: Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment. J Med Genet 39 (7): 526-30, 2002.  [PUBMED Abstract]
   
   
2. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 14 (5): 1730-6; discussion 1737-40, 1996.  [PUBMED Abstract]
   
   
3. Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed September 16, 2004. 
   
   
4. Grann VR, Jacobson JS: Population screening for cancer-related germline gene mutations. Lancet Oncol 3 (6): 341-8, 2002.  [PUBMED Abstract]
   
   
5. Genetic counseling. Am J Hum Genet 27 (2): 240-2, 1975.  [PUBMED Abstract]
   
   
6. Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998. 
   
   
7. Bartels DM, LeRoy BS, Caplan AL, eds.: Prescribing Our Future: Ethical Challenges in Genetic Counseling. New York, NY: Aldine de Gruyter, 1993. 
   
   
8. Kenen RH: Genetic counseling: the development of a new interdisciplinary occupational field. Soc Sci Med 18 (7): 541-9, 1984.  [PUBMED Abstract]
   
   
9. Kenen RH, Smith AC: Genetic counseling for the next 25 years: models for the future. J Genet Couns 4(2): 115-124, 1995. 
   
   
10. Woolf SH: Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 333 (21): 1401-5, 1995.  [PUBMED Abstract]
    
    
11. Winawer SJ, Fletcher RH, Miller L, et al.: Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112 (2): 594-642, 1997.  [PUBMED Abstract]
    
    

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