Cancer Genetics Overview (PDQ®)–Health Professional Version

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Introduction

[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 Table 1, Variant Classification for Pathogenicity for more information.]

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 pathogenic variant as the cause of inherited risk and to determine whether family members have inherited the disease-related variant.

The proportion of individuals carrying a pathogenic variant 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 inFigure 1. For adult-onset diseases, penetrance is usually described by the individualcarrier's age and sex. For example, the penetrance for breast cancer in female carriers ofBRCA1/BRCA2 pathogenic variants 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 carrier's risk of cancer involves some level of imprecision.

Graph shows relative risk on the x-axis and allele frequency on the y-axis. A line depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants and a higher relative risk associated with rare, high-penetrance genetic variants. — 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 pathogenic variants in the *BRCA1*/*BRCA2* genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.

Genetic variants, or changes in the usual DNA sequence of a particular gene, can have harmful, beneficial, neutral, or uncertain effects on health and may be inherited asautosomal dominant, autosomal recessive, or X-linked traits. Pathogenic variants that cause serious disability early in life are usually rare because of their adverse effect on life expectancy and reproduction. However, if the pathogenic variant is autosomal recessive—that is, if the health effect of the variant is caused only when two copies (one from each parent) of the altered gene are inherited— carriers of the pathogenic variant (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. Pathogenic variants that cause health effects in middle and older age, including several pathogenic variants 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 pathogenic variant. (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 familialand 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 forgenetic 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:

In the individual patient:
- Multiple primary tumors in the same organ.
- Multiple primary tumors in different organs.
- Bilateral primary tumors in paired organs.
- Multifocality within a single organ (e.g., multiple tumors in the same breast, all of which have risen from one original tumor).
- Younger-than-usual age at tumor diagnosis.
- Tumors with rare histology.
- Tumors occurring in the sex not usually affected (e.g., breast cancer in men).
- Tumors associated with other genetic traits.
- Tumors associated with congenital defects.
- Tumors associated with an inherited precursor lesion.
- Tumors associated with another rare disease.
- Tumors associated with cutaneous lesions known to be related to cancer susceptibility disorders (e.g., the genodermatoses).
In the patient’s family:
- One first-degree relative with the same or a related tumor and one of the individual features listed.
- Two or more first-degree relatives with tumors of the same site.
- Two or more first-degree relatives with tumor types belonging to a known familial cancer syndrome.
- Two or more first-degree relatives with rare tumors.
- Three or more relatives in two generations with tumors of the same site or etiologically related sites.

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 variant 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 variant. 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 variant 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 carrier status without being directly tested, for example, when a biological parent of a child who is a known carrier of a pathogenic variant is identified as an obligate carrier. Founder effects may result in the recognition that specific ethnic groups have a higher prevalence of certain pathogenic variants, 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.

References

Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008. [PUBMED Abstract]

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Genetic Counseling