[Note: Many 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.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

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 minds open to new improved information as it comes along.

The quality of evidence depends on the appropriateness of the study in terms of 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 studies) 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 treatment or risk 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.

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 genetic variant 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 variants, the study populations used for each risk assessment will be noted, according to the following categories.

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:

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 cutoff 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.

References

1. 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]
2. Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003. [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. Johns Hopkins Press, 1998. Also available online. Last accessed November 5, 2020.

Analytic validity refers to how well a genetic assessment measures 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 pathogenic variant, analytic validity refers to the accuracy of a genetic test in identifying the presence or absence of the variant. The technical accuracy and reliability of the testing procedure and the quality of the laboratory processes (including specimen handling) affect the analytic validity of a genetic assessment.

Assessing analytic validity is complex for some genetic tests. For example, in a panel test, which is designed to evaluate a particular set of variants (e.g., the Ashkenazi founder pathogenic variants in the BRCA1 and BRCA2 genes), 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 pathogenic variants are present (including variants 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 pathogenic variants 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). It 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 people who test positive for a clinical condition among those who actually have the clinical condition; specificity refers to the proportion of people who test negative for a clinical condition among 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 genetic variant itself but also by any other modifying factors that might affect the penetrance of the variant (e.g., the carrier's environmental exposures or personal behaviors) or by the presence or absence of variants in other genes. For this reason, the clinical validity of a genetic test for a specific genetic variant may vary in different populations. If the cancer risk associated with a given variant is unknown or variable, a test for the variant 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.[1] 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 and unaffected people in a series of families; or 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 pathogenic variant or the magnitude of risk and lifetime probability of cancer conferred by a pathogenic variant 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 risk associated with a pathogenic variant 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.

References

1. Grann VR, Jacobson JS: Population screening for cancer-related germline gene mutations. Lancet Oncol 3 (6): 341-8, 2002. [PUBMED Abstract]

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 people 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:

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) should be considered when evaluating interventions. Sometimes genetic information may lead clinicians to consider changes in their approach to clinical management, based on expert opinion, in the absence of proof of clinical utility.

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.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.