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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
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.
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 of identifying 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.
The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 1. For adult-onset diseases, penetrance is usually described by the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision. Figure 1. Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as mutations in the BRCA1/ BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.
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), 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 either 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.
Genetic 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 the following 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 an unknown number of 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.
Individual PDQ summaries focused on the genetics of specific cancers contain detailed information about many known cancer susceptibility syndromes. Although this is not a complete list, the following cancer susceptibility syndromes are discussed in the PDQ cancer genetics summaries (listed in parentheses following the syndromes):
The recognition that cancer clusters within families has led many investigators to collect data on multiple-case families with the goal of localizing cancer susceptibility genes through linkage studies.
Linkage studies are typically performed on high-risk kindreds, in whom multiple cases of a particular disease have occurred, in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:
An additional issue in linkage studies is the background rate of sporadic cancer in the context of family studies. For example, because a man's lifetime risk of prostate cancer is one in six, it is possible that families under study have both inherited and sporadic prostate cancer cases. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer.
One way to address inconsistencies between linkage studies is to require inclusion criteria that defines clinically significant disease.[2,3,4] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.
Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[5,6] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[7,8]
Genome-wide Association Studies (GWAS)
GWAS are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including cancer. This approach can be contrasted with linkage analysis, which searches for genetic-risk variants cosegregating within families that have a high prevalence of disease. While linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial), GWAS are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given population (e.g., men of European ancestry). GWAS capture a large portion of common variation across the genome.[10,11] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to "scan" the genome without having to test all 10 million known single nucleotide polymorphisms (SNPs). With GWAS, researchers can test 500,000 to 1 million SNPs per study and ascertain almost all common inherited variants in the genome.
In a GWAS, allele frequency for each SNP is compared between cases and controls. Promising signals—in which allele frequencies deviate significantly in case and control populations—are validated in replication cohorts. To have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because up to 1 million SNPs are evaluated in a GWAS, false-positive findings are expected to occur frequently when using standard statistical thresholds. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 × 10-7.[12,13,14]
To date, well over 100 cancer-risk variants have been identified by well-powered GWAS and validated in independent cohorts. These studies have revealed convincing associations between specific inherited variants and cancer risk. However, the findings should be qualified with a few important considerations:
The implications of these points are discussed in greater detail in the PDQ summaries on Genetics of Breast and Ovarian Cancer; Genetics of Colorectal Cancer; and Genetics of Prostate Cancer. Additional details can be found elsewhere.
PDQ 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.
Refer to the Levels of Evidence for Cancer Genetics Studies summary for more information on the levels of evidence utilized in the PDQ cancer genetics summaries.
Health care providers who deliver genetic services, including genetic counseling, can be located through local, regional, and national professional genetics organizations and through NCI's Cancer Genetics Services Directory 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, pediatricians, 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.
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 NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer genetics. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Cancer Genetics Overview. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/genetics/overview/healthprofessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2013-07-31
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