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Cancer Genetics Overview (PDQ®): Genetics - Health Professional Information [NCI]Purpose of This PDQ SummaryThis PDQ cancer information summary for health professionals provides a framework for understanding the genetic basis of hereditary cancer. This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board. Information about the following is included in this summary:
The PDQ Cancer Genetics summaries contain level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how the level of evidence designations are made is described in detail in this summary. This summary does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations. IntroductionMany of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window. The etiology of cancer is multifactorial, with genetic, environmental, medical, and lifestyle factors interacting to produce a given malignancy. Knowledge of cancer genetics is rapidly improving our understanding of cancer biology, helping to identify at-risk individuals, furthering the ability to characterize malignancies, establishing treatment tailored to the molecular fingerprint of the disease, and leading to the development of new therapeutic modalities. As a consequence, this expanding knowledge base has implications for all aspects of cancer management, including prevention, screening, and treatment. Genetic information provides a means to identify people who have an increased risk of cancer. Sources of genetic information include biologic samples of DNA, information derived from a person's family history of disease, findings from physical examinations, and medical records. DNA-based information can be gathered, stored, and analyzed at any time during an individual's life span, from before conception to after death. Family history may identify people with a modest to moderately increased risk of cancer or may serve as the first step in the identification of an inherited cancer predisposition that confers a very high lifetime risk of cancer. For an increasing number of diseases, DNA-based testing can be used to identify a specific mutation as the cause of inherited risk and to determine whether family members have inherited the disease-related mutation. Throughout this summary, the term "mutation" will be used to refer to a change in the usual DNA sequence of a particular gene. Mutations can have harmful, beneficial, neutral, or uncertain 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 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 (one from each parent) of the mutated gene are inherited—mutation carriers (healthy people carrying one copy of the altered gene) may be relatively common in the general population. "Common" in this context refers, by convention, to a prevalence of 1% or more. Mutations that cause health effects in middle and older age, including several mutations known to cause a predisposition to cancer, may also be relatively common. Many cancer-predisposing traits are inherited in an autosomal dominant fashion, that is, the cancer susceptibility occurs when only one copy of the altered gene is inherited. For autosomal dominant conditions, the term "carrier" is often used in a less formal manner to denote people who have inherited the genetic predisposition conferred by the mutation. Refer to individual PDQ summaries focused on the genetics of specific cancers for detailed information on known cancer-susceptibility syndromes. Increasingly, the public is turning to the Internet for information related both to familial and genetic susceptibility to cancer and to genetic risk assessment and testing. Direct-to-consumer marketing of genetic testing for hereditary breast and colon cancer is also taking place in some communities. This wider availability of information related to inherited cancer risk may raise concerns among persons previously unaware of the implications inherent in their family histories and may lead some of these individuals to consult their primary care physicians for management advice and recommendations. In many instances, the evaluation and advice will be relatively straightforward for physicians with a basic knowledge of familial cancer. In a subset of patients, the evaluation may be more complex, calling for referral to genetics professionals for further evaluation and counseling. Correctly recognizing and identifying individuals and families at increased risk of developing cancer is one of countless important roles for primary care and other health care providers. Once identified, these individuals can then be appropriately referred for genetic counseling, risk assessment, consideration of genetic testing, and development of a management plan. When medical and family histories reveal cardinal clues to the presence of an underlying familial or genetic cancer susceptibility disorder (see list below),[1] further evaluation may be warranted. Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about the components of a genetics cancer risk assessment. Features of hereditary cancer include the following:
Concluding that an individual is at increased risk of developing cancer may have important, potentially life-saving management implications and may lead to specific interventions aimed at reducing risk (e.g., tamoxifen for breast cancer, colonoscopy for colon cancer, or risk-reducing salpingo-oophorectomy for ovarian cancer). Information about familial cancer risk may also inform a person's ability to plan for the future (lifestyle and health care decisions, family planning, or other decisions). Genetic information may also provide a direct health benefit by demonstrating the lack of an inherited cancer susceptibility. For example, if a family is known to carry a cancer-predisposing mutation in a particular gene, a family member may experience reduced worry and lower health care costs if his or her genetic test indicates that he or she does not carry the family's disease-related mutation. Conversely, information about familial cancer risk may have psychological effects or social costs (e.g., worry, guilt, or increased health care costs). Family dynamics also may be affected. For instance, the involvement of one or more family members may be required for genetic testing to be informative, and parents may feel guilt about passing inherited risk on to their children. Knowledge about a cancer-predisposing mutation can be informative not only for the individual tested but also for other family members. Family members who previously had not considered the implications of their family history for their own health may be led to do so, and some will undergo genetic testing, resulting in more definitive information on whether they are at increased genetic risk. Some relatives may learn their mutation status without being directly tested, for example, when a biological parent of a child who is a known mutation carrier is identified as an obligate carrier. Founder effects may result in the recognition that specific ethnic groups have a higher prevalence of certain mutations, knowledge that can be both clinically useful (permitting more rational genetic testing strategies) or potentially stigmatizing. Testing may reveal the presence of nonpaternity in a family. There is the theoretical possibility that genetic information may be misused, and concerns about the potential for insurance and/or employment discrimination may arise. Genetic information may also affect medical and lifestyle decisions. Refer to individual PDQ summaries for available evidence addressing all ancillary issues. References:
CounselingGenetic counseling is a process of communication between genetics professionals and patients with the goal of providing individuals and families with information on the relevant aspects of their genetic health, available testing and management options, and support as they move toward understanding and incorporating this information into their daily lives. Genetic counseling generally involves six steps:
Genetic evaluation involves an interaction with a medical geneticist or other genetics professional and may include a physical examination and diagnostic testing, in addition to genetic counseling. The principles of voluntary and informed decision making, nondirective and noncoercive counseling, and protection of client confidentiality and privacy are central to the philosophy of genetic counseling.[1,2,3,4,5] Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information on the nature and history of genetic counseling. From the mid 1990s to the mid 2000s, 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 that may include a genetic counselor, an advanced practice genetics nurse, or a medical geneticist; a mental health professional; and various medical experts such as an oncologist, surgeon, or internist. The process of counseling may require a number of visits to address 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 accurate family and medical histories. Cancer genetic counseling may involve several family members, some of whom will have had cancer and others who have not. The impact of risk assessment and predisposition genetic testing is improved health outcomes. The information derived from risk assessment and/or genetic testing allows the health care provider to tailor an individual approach to health promotion and optimize long-term health outcomes through the identification of at-risk individuals before cancer develops. The health care provider can thus intervene earlier either to reduce the risk or diagnose a cancer at an earlier stage, when the chances for effective treatment are greatest. The information may be used to modify the management approach to an initial cancer, clarify the risks of other cancers, or predict the response of an existing cancer to specific forms of treatment, all of which may alter treatment recommendations and long-term follow-up. References:
Structure and Content of PDQ SummariesPDQ cancer genetics summaries focus on the genetics of specific cancers, inherited cancer syndromes, and the ethical, social, and psychological implications of cancer genetics knowledge. Sections on the genetics of specific cancers include syndrome-specific information on the risk implications of a family history of cancer, the prevalence and characteristics of cancer-predisposing mutations, 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. The source of medical literature cited in PDQ cancer genetics summaries is peer-reviewed scientific publications, the quality and reliability of which is evaluated in terms of levels of evidence. Where relevant, the level of evidence is cited, or particular strengths of a study or limitations of the evidence are described. Creating evidence-based summaries on 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 areas of medicine, testing and treatment decisions must be based on information that sometimes falls short of the optimal level of evidence. Recognizing the limits inherent in certain observations will alter the weight given to recommendations based on that evidence and serves to keep our minds open to new improved information, as it comes along. The quality of evidence depends on the appropriateness of the study to the question being evaluated and on how well the study was designed, implemented, analyzed, and interpreted. For evaluating outcomes of both medical and social interventions, the strongest evidence is obtained from well-designed and well-conducted randomized clinical trials. For evaluating other questions, particularly those related to the prevalence of gene variants and inherited syndromes and determining the clinical validity of genetic tests, the strongest evidence is obtained from well-designed descriptive studies. Particular elements of study design, such as the nature of the population studied or the duration of observation, may be crucial to assessing the quality of a study. During the 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, including well-designed quasi-experimental studies (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 management decisions before full data on the risks and benefits of cancer genetic testing are available. In addition, such work helps to inform future research using more rigorous designs. Study Populations The level of evidence required for informed decision making about genetic testing 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 is likely to be insufficient to make early recommendations for, or decisions about, testing in families with less dramatic histories or in the general population. Even among people with similar family histories, however, other contributing genes or different exposures could modify the effect of a gene mutation in different families. 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 genetic polymorphisms and mutations, the study populations used for each risk assessment will be noted, according to the following categories.
Use of Levels of Evidence The PDQ editorial boards use a ranking system of levels of evidence to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. For any given therapy, results of prevention and treatment studies can be ranked on each of the following two scales: (1) strength of the study design and (2) strength of the endpoints. Together, the two rankings provide a measure of the overall level of evidence. Screening studies are ranked on strength of study design alone. Depending on perspective, different expert panels, professional organizations, or individual physicians may use different cut-off points related to overall strength of evidence in formulating therapeutic guidelines or in taking action; however, a formal description of the level of evidence provides a uniform framework for the data, leading to specific recommendations. There are varying levels of evidence related to screening, prevention, and treatment that support a given summary. The summaries are subject to modification as new evidence becomes available. The strongest evidence would be that obtained from a well-designed and well-conducted randomized controlled trial. It is not always practical, however to conduct such a trial to address every question in the fields of cancer screening, prevention, and treatment. Evidence related to screening The PDQ Cancer Genetics Editorial Board has adopted the following definitions related to screening:
Five requirements should be met before it is considered appropriate to screen for a particular medical condition as part of routine medical practice:[1,2]
In order of strength of evidence, the levels for screening studies follow:
Evidence related to cancer prevention Prevention is defined as a reduction in the incidence (or the rate) of new cancer, with the goal of reducing cancer-related morbidity and mortality. Examples of prevention strategies include smoking cessation, avoidance of excessive exposure to sunlight (ultraviolet) or ionizing radiation, surgical removal of an at-risk target organ before cancer develops, and use of medications (e.g., tamoxifen for breast cancer risk reduction). For each prevention-related summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the five levels are as follows:
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] Evidence related to treatment For each treatment-related summary of evidence statement, the associated levels of evidence are listed. In order of strength of evidence, the five levels are as follows:
Analytic Validity 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 reported 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. The analytic validity of a genetic test is affected by the technical accuracy and reliability of the testing procedure and by the quality of the laboratory processes (including specimen handling). The assessment of analytic validity is complex for some genetic tests. For example, a panel test is designed to evaluate a particular set of mutations (e.g., the Ashkenazi founder mutations in the BRCA1 and BRCA2 genes), and the analytic validity of the different components of the test may vary. Some genetic tests involve evaluating the DNA sequence of portions of a gene to determine whether any mutations are present (including mutations not previously identified). 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 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 primarily determined by the sensitivity and specificity with which a test identifies people with a defined clinical condition within a given population. Sensitivity of a test refers to the proportion of persons who test positive among all those who actually have a clinical condition; specificity refers to the proportion of persons who test negative from among all those who do not have the clinical condition. In the case of genetic susceptibility to cancer, clinical validity can be considered at two levels:
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 mutation itself but also by any other modifying factors that might affect the penetrance of the mutation (e.g., the mutation carrier's environmental exposures or personal behaviors) or 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. Clues to whether a particular familial cancer syndrome has a genetic basis can be derived informally, by inspecting the pattern of affected persons and unaffected persons in a series of families; or more formally, using an analytic technique known as segregation analysis. Segregation analysis provides quantitative data in support of, or against, the likelihood that a particular genetic mode of inheritance might explain the patterns observed in the study families. Evidence that a particular gene might explain a specific cancer predisposition syndrome often derives initially from linkage studies that use collections of families meeting stringent clinical criteria for a specific cancer susceptibility syndrome. The demonstration of strong linkage of cancer susceptibility to a gene or genetic region in a pattern consistent with autosomal dominant inheritance provides evidence in support of both the mode of inheritance and the particular gene that might underlie the risk. 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 may not be representative of the general population. The genetic trait measured in linkage studies is not always the causal factor itself but may 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 general 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 in the general population can best be assessed by direct study of those populations. Clinical Utility 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 related to the interventions offered to persons with positive test results. Theoretically, there are at least five strategies that might improve the health outcome of people with a genetic susceptibility to cancer:
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. References:
Genetic ResourcesHealth care providers who deliver genetic services, including genetic counseling can be located through local, regional, and national professional genetics organizations; through the NCI Web site Cancer Genetics Services Directory; and through the Gene Tests-Gene Clinics Web site. Providers of cancer genetic services are not limited to one specialty and include medical geneticists, genetic counselors, advanced practice genetics nurses, oncologists (medical, radiation, or surgical), other surgeons, internists, family practitioners, and mental health professionals. A cancer genetics health care provider will assist in constructing and evaluating a pedigree, eliciting and evaluating personal and family medical histories, and calculating and providing information about cancer risk and/or probability of a mutation being associated with cancer in the family. In addition, if a genetic test is available, these providers can assist in pretest counseling, laboratory selection, informed consent, test interpretation, posttest counseling, and follow-up. Please see the Table of Links at the end of this summary in printable view for the Genetic Resources URLs. Clinical Genetics
Consumer/Client: General Information
Ethical, Legal and Social Implications (ELSI), Policy, and Legislation
Family History Tools
Genome Research
Health Professional Practice and Education
Institutional Review Boards (IRBs)
Professional Organizations: Genetics
Risk Assessment
Online Gene Mutation Prediction Programs
Search Engines Specializing in Genetics and Genomics
United States Government Agencies
Get More Information From NCICALL 1-800-4-CANCER For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. A trained Cancer Information Specialist is available to answer your questions. CHAT ONLINE The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer. WRITE TO US For more information from the NCI, please write to this address:
SEARCH THE NCI WEB SITE The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered. There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment. FIND PUBLICATIONS The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237). Changes to This Summary (10 / 05 / 2009)The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above. GENETICS RESOURCES Added the Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators as health professional practice and education resource that establishes a minimum basis to prepare the nursing workforce to deliver competent genetic and genomic-focused nursing care. Added the Catalog of Published Genome-Wide Association Studies as an online resource of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs. More InformationABOUT PDQ
ADDITIONAL PDQ SUMMARIES
IMPORTANT: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). Date Last Modified: 2009-10-05
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