What is genetic testing?
Genetic testing looks for specific inherited changes (mutations) in a person’s chromosomes, genes, or proteins. Genetic mutations can have harmful, beneficial, neutral (no effect), or uncertain effects on health. Mutations that are harmful may increase a person’s chance, or risk, of developing a disease such as cancer. Overall, inherited mutations are thought to play a role in about 5 to 10 percent of all cancers.
Cancer can sometimes appear to “run in families” even if it is not caused by an inherited mutation. For example, a shared environment or lifestyle, such as tobacco use, can cause similar cancers to develop among family members. However, certain patterns—such as the types of cancer that develop, other non-cancer conditions that are seen, and the ages at which cancer typically develops—may suggest the presence of a hereditary cancer syndrome.
The genetic mutations that cause many of the known hereditary cancer syndromes have been identified, and genetic testing can confirm whether a condition is, indeed, the result of an inherited syndrome. Genetic testing is also done to determine whether family members without obvious illness have inherited the same mutation as a family member who is known to carry a cancer-associated mutation.
Inherited genetic mutations can increase a person’s risk of developing cancer through a variety of mechanisms, depending on the function of the gene. Mutations in genes that control cell growth and the repair of damaged DNA are particularly likely to be associated with increased cancer risk.
Does someone who inherits a cancer-predisposing mutation always get cancer?
No. Even if a cancer-predisposing mutation is present in a family, it does not necessarily mean that everyone who inherits the mutation will develop cancer. Several factors influence the outcome in a given person with the mutation.
One factor is the pattern of inheritance of the cancer syndrome. To understand how hereditary cancer syndromes may be inherited, it is helpful to keep in mind that every person has two copies of most genes, with one copy inherited from each parent. Most mutations involved in hereditary cancer syndromes are inherited in one of two main patterns: autosomal dominant and autosomal recessive.
With autosomal dominant inheritance, a single altered copy of the gene is enough to increase a person’s chances of developing cancer. In this case, the parent from whom the mutation was inherited may also show the effects of the gene mutation. The parent may also be referred to as a carrier.
With autosomal recessive inheritance, a person has an increased risk of cancer only if he or she inherits a mutant (altered) copy of the gene from each parent. The parents, who each carry one copy of the altered gene along with a normal (unaltered) copy, do not usually have an increased risk of cancer themselves. However, because they can pass the altered gene to their children, they are called carriers.
A third form of inheritance of cancer-predisposing mutations is X-linked recessive inheritance. Males have a single X chromosome, which they inherit from their mothers, and females have two X chromosomes (one from each parent). A female with a recessive cancer-predisposing mutation on one of her X chromosomes and a normal copy of the gene on her other X chromosome is a carrier but will not have an increased risk of cancer. Her sons, however, will have only the altered copy of the gene and will therefore have an increased risk of cancer.
Even when people have one copy of a dominant cancer-predisposing mutation, two copies of a recessive mutation, or, for males, one copy of an X-linked recessive mutation, they may not develop cancer. Some mutations are “incompletely penetrant,” which means that only some people will show the effects of these mutations. Mutations can also “vary in their expressivity,” which means that the severity of the symptoms may vary from person to person.
More than 50 hereditary cancer syndromes have been described. The majority of these are caused by highly penetrant mutations that are inherited in a dominant fashion. The list below includes some of the more common inherited cancer syndromes for which genetic testing is available, the gene(s) that are mutated in each syndrome, and the cancer types most often associated with these syndromes.
Hereditary breast cancer and ovarian cancer syndrome
- Genes: BRCA1, BRCA2
- Related cancer types: Female breast, ovarian, and other cancers, including prostate, pancreatic, and male breast cancer
- Gene: TP53
- Related cancer types: Breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia, brain tumors, adrenocortical carcinoma (cancer of the adrenal glands), and other cancers
- Gene: PTEN
- Related cancer types: Breast, thyroid, endometrial (uterine lining), and other cancers
Lynch syndrome (hereditary nonpolyposis colorectal cancer)
- Genes: MSH2, MLH1, MSH6, PMS2, EPCAM
- Related cancer types: Colorectal, endometrial, ovarian, renal pelvis, pancreatic, small intestine, liver and biliary tract, stomach, brain, and breast cancers
- Gene: APC
- Related cancer types: Colorectal cancer, multiple non-malignant colon polyps, and both non-cancerous (benign) and cancerous tumors in the small intestine, brain, stomach, bone, skin, and other tissues
- Gene: RB1
- Related cancer types: Eye cancer (cancer of the retina), pinealoma (cancer of the pineal gland), osteosarcoma, melanoma, and soft tissue sarcoma
Multiple endocrine neoplasia type 1 (Wermer syndrome)
- Gene: MEN1
- Related cancer types: Pancreatic endocrine tumors and (usually benign) parathyroid and pituitary gland tumors
- Gene: RET
- Related cancer types: Medullary thyroid cancer and pheochromocytoma (benign adrenal gland tumor)
- Gene: VHL
- Related cancer types: Kidney cancer and multiple noncancerous tumors, including pheochromocytoma
Who should consider genetic testing for cancer risk?
Many experts recommend that genetic testing for cancer risk should be strongly considered when all three of the following criteria are met:
- The person being tested has a personal or family history that suggests an inherited cancer risk condition
- The test results can be adequately interpreted (that is, they can clearly tell whether a specific genetic change is present or absent)
- The results provide information that will help guide a person’s future medical care
The features of a person’s personal or family medical history that, particularly in combination, may suggest a hereditary cancer syndrome include:
- Cancer that was diagnosed at an unusually young age
- Several different types of cancer that have occurred independently in the same person
- Cancer that has developed in both organs in a set of paired organs, such as both kidneys or both breasts
- Several close blood relatives that have the same type of cancer (for example, a mother, daughter, and sisters with breast cancer)
- Unusual cases of a specific cancer type (for example, breast cancer in a man)
- The presence of birth defects, such as certain noncancerous (benign) skin growths or skeletal abnormalities, that are known to be associated with inherited cancer syndromes
- Being a member of a racial/ethnic group that is known to have an increased chance of having a certain hereditary cancer syndrome and having one or more of the above features as well
It is strongly recommended that a person who is considering genetic testing speak with a professional trained in genetics before deciding whether to be tested. These professionals can include doctors, genetic counselors, and other health care providers (such as nurses, psychologists, or social workers). Genetic counseling can help people consider the risks, benefits, and limitations of genetic testing in their particular situation. Sometimes the genetic professional finds that testing is not needed.
Genetic counseling includes a detailed review of the individual’s personal and family medical history related to possible cancer risk. Counseling also includes discussions about such issues as:
- Whether genetic testing is appropriate, which specific test(s) might be used, and the technical accuracy of the test(s)
- The medical implications of a positive or a negative test result (see below)
- The possibility that a test result might not be informative—that is, that the information may not be useful in making health care decisions (see below)
- The psychological risks and benefits of learning one’s genetic test results
- The risk of passing a genetic mutation (if one is present in a parent) to children
Learning about these issues is a key part of the informed consent process. Written informed consent is strongly recommended before a genetic test is ordered. People give their consent by signing a form saying that they have been told about, and understand, the purpose of the test, its medical implications, the risks and benefits of the test, possible alternatives to the test, and their privacy rights.
Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person’s relatives. The presence of a harmful genetic mutation in one family member makes it more likely that other blood relatives may also carry the same mutation. Family relationships can be affected when one member of a family discloses genetic test results that may have implications for other family members. Family members may have very different opinions about how useful it is to learn whether they do or do not have a disease-related genetic mutation. Health discussions may get complicated when some family members know their genetic status while other family members do not choose to know their test results. A conversation with genetics professionals may help family members better understand the complicated choices they may face.
How is genetic testing done?
Genetic tests are usually requested by a person’s doctor or other health care provider or the person himself. Although it may be possible to obtain some genetic tests without a health care provider’s order, this approach is not recommended because it does not give the patient the valuable opportunity to discuss this complicated decision with a knowledgeable professional. If you do, please hire a genetic counselor to read the results.
Testing is done on a small sample of body fluid or tissue—usually blood, but sometimes saliva, cells from inside the cheek, skin cells, or amniotic fluid (the fluid surrounding a developing fetus).
The sample is then sent to a laboratory that specializes in genetic testing. The laboratory returns the test results to the doctor or genetic counselor who requested the test. In some cases, the laboratory may send the results to the patient directly. It usually takes several weeks or longer to get the test results. Genetic counseling is recommended both before and after genetic testing to make sure that patients have accurate information about what a particular genetic test means for their health and care.
Genetic testing can have several possible results: positive, negative, true negative, uninformative negative, false negative, variant of unknown significance, or benignpolymorphism. These results are described below.
- Confirm the diagnosis of a hereditary cancer syndrome
- Indicate an increased risk of developing certain cancer(s) in the future
- Show that someone carries a particular genetic change that does not increase their own risk of cancer but that may increase the risk in their children if they also inherit an altered copy from their other parent (that is, if the child inherits two copies of the abnormal gene, one from their mother and one from their father).
- Suggest a need for further testing
- Provide important information that can help other family members make decisions about their own health care.
Also, people who have a positive test result that indicates that they have an increased risk of developing cancer in the future may be able to take steps to lower their risk of developing cancer or to find cancer earlier, including:
- Being checked at a younger age or more often for signs of cancer
- Reducing their cancer risk by taking medications or having surgery to remove “at-risk” tissue (These approaches to risk reduction are options for only a few inherited cancer syndromes.)
- Changing personal behaviors (like quitting smoking, getting more exercise, and eating a healthier diet) to reduce the risk of certain cancers
A positive result on a prenatal genetic test for cancer risk may influence a decision about whether to continue a pregnancy. The results of pre-implantation testing (performed on embryos created by in vitro fertilization) can guide a doctor in deciding which embryo (or embryos) to implant in a woman’s uterus.
Finally, in patients who have already been diagnosed with cancer, a positive result for a mutation associated with certain hereditary cancer syndromes can influence how the cancer is treated. For example, some hereditary cancer disorders interfere with the body’s ability to repair damage that occurs to cellular DNA. If someone with one of these conditions receives a standard dose of radiation or chemotherapy to treat their cancer, they may experience severe, potentially life-threatening treatment side effects. Knowing about the genetic disorder before treatment begins allows doctors to modify the treatment and reduce the severity of the side effects.
A “negative test result” means that the laboratory did not find the specific alteration that the test was designed to detect. This result is most useful when working with a family in which the specific, disease-causing genetic alteration is already known to be present. In such a case, a negative result can show that the tested family member has not inherited the mutation that is present in their family and that this person therefore does not have the inherited cancer syndrome tested for, does not have an increased genetic risk of developing cancer, or is not a carrier of a mutation that increases cancer risk. Such a test result is called a “true negative.” A true negative result does not mean that there is no cancer risk, but rather that the risk is probably the same as the cancer risk in the general population.
When a person has a strong family history of cancer but the family has not been found to have a known mutation associated with a hereditary cancer syndrome, a negative test result is classified as an “uninformative negative” (that is, does not provide useful information). It is not possible to tell whether someone has a harmful gene mutation that was not detected by the particular test used (a “false negative”) or whether the person truly has no cancer-predisposing genetic alterations in that gene. It is also possible for a person to have a mutation in a gene other than the gene that was tested.
If genetic testing shows a change that has not been previously associated with cancer in other people, the person’s test result may report “variant of unknown significance,” or VUS. This result may be interpreted as “ambiguous” (uncertain), which is to say that the information does not help in making health care decisions.
If the test reveals a genetic change that is common in the general population among people without cancer, the change is called a polymorphism. Everyone has commonly occurring genetic variations (polymorphisms) that are not associated with any increased risk of disease.
A genetic counselor, doctor, or other health care professional trained in genetics can help an individual or family understand their test results. Such counseling may include discussing recommendations for preventive care and screening with the patient, referring the patient to support groups and other information resources, and providing emotional support to the person receiving the results.
In some cases, a genetic counselor or doctor may recommend that other family members consider being tested for specific gene changes that indicate an increased risk of cancer. The decision to test other family members is complicated. It requires a careful evaluation of family history and other factors as well as advice from a genetic counselor or other professional trained in genetics. In general, physicians rely on the family member who has been tested to share the genetic information with their relatives so that family members will know that a genetic condition has been identified in their family. Then, each family member will need to make their own decision regarding whether or not to be tested themselves.
Medical test results are normally included in a person’s medical records, particularly if a doctor or other health care provider has ordered the test or has been consulted about the test results. Therefore, people considering genetic testing must understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their insurance company or employer, if their employer provides the patient’s health insurance as a benefit.
However, legal protections are in place to prevent genetic discrimination, which would occur if insurance companies or employers were to treat people differently because they have a gene mutation that increases their risk of a disease such as cancer or because they have a strong family history of a disease such as cancer.
In 2008, the Genetic Information Nondiscrimination Act (GINA) became federal law for all U.S. residents. GINA prohibits discrimination based on genetic information in determining health insurance eligibility or rates and suitability for employment. However, GINA does not cover members of the military, and it does not apply to life insurance, disability insurance, or long-term care insurance. Some states have additional genetic nondiscrimination legislation that addresses the possibility of discrimination in those contexts.
In addition, because a person’s genetic information is considered one kind of health information, it is covered by the Privacy Rule of the Health Information Portability and Accountability Act (HIPAA) of 1996. The Privacy Rule requires that health care providers and others with medical record access protect the privacy of health information, sets limits on the use and release of health records, and empowers people to control certain uses and sharing of their health-related information. Many states also have laws to protect patient privacy and limit the release of genetic and other health information. The National Human Genome Research Institute Genetic Discrimination page includes links to more information about GINA, HIPAA, and other legislation related to genetic discrimination in insurance or employment.
Some companies offer at-home genetic testing, also known as direct-to-consumer (DTC) genetic testing. People collect a tissue sample themselves and submit the sample through the mail. They learn about the test results online, by mail, or over the phone. DTC genetic testing is often done without a doctor’s order or guidance from a doctor or genetic counselor before the test. Some states in the United States do not allow DTC genetic testing.
Whereas the genetic testing for cancer that is typically ordered by a doctor involves testing for rare major hereditary cancer syndromes, most DTC genetic testing for cancer risk involves the analysis of common inherited genetic variants, called single-nucleotide polymorphisms, that have been shown to be statistically associated with a particular type of cancer. Each individual variant is generally associated with only a minor increase in risk, and even when added together all the known variants for a particular cancer type account for only a small portion of a person’s risk of that cancer. Although the identification and study of such variants is an active area of research, genetic tests based on these variants have not yet been found to help patients and their care providers make health care decisions and, therefore, they are not a part of recommended clinical practice.
Even when people have DTC genetic tests for known mutations in genes associated with hereditary cancer syndromes, there are potential risks and drawbacks to the use of DTC testing. In particular, without guidance about genetic test results from an informed, genetically knowledgeable health care provider, people may experience unneeded anxiety or false reassurance, or they may make important decisions about medical treatment or care based on incomplete information.
Also, although some people may view DTC genetic testing as a way to ensure the privacy of their genetic test results, companies that offer DTC genetic testing do not always tell the consumer the details of their privacy policies. In addition, if people consult their doctor or other health care provider about the test results obtained from a DTC testing vendor, the results may become part of the patient’s medical record anyway. Also, companies that provide DTC testing may not be subject to current state and federal privacy laws and regulations. It is generally recommended that people considering DTC genetic testing make sure that they have chosen a reputable company.
The U.S. Federal Trade Commission (FTC) has a fact sheet about at-home genetic tests which offers advice for people who are considering such a test. As part of its mission, the FTC investigates complaints about false or misleading health claims in advertisements.
The American Society of Human Genetics, a membership organization of genetics professionals, has issued a statement about DTC genetic tests that recommends transparency in such testing, provider education about the testing, and the development of appropriate regulations to ensure test and laboratory quality.
U.S. laboratories that perform health-related testing, including genetic testing, are regulated under the Clinical Laboratory Improvement Amendments (CLIA) program. Laboratories that are certified under CLIA are required to meet federal standards for quality, accuracy, and reliability of tests. All laboratories that do genetic testing and share results must be CLIA certified. However, CLIA certification only indicates that appropriate laboratory quality control standards are being followed; it does not guarantee that a genetic test being done by a laboratory is medically useful.
The Centers for Medicare and Medicaid Services has more information about CLIA programs. The National Library of Medicine also has information about how genetic testing is regulated and how to judge the quality of a genetic test. This information is available in the Genetics Home Reference.
Research to find newer and better ways of detecting, treating, and preventing cancer in people who carry genetic mutations that increase the risk of certain cancers is ongoing. Scientists are also doing studies to find additional genetic changes that can increase a person’s risk of cancer.
NCI runs an active program of genome-wide association studies (GWAS) through its Cancer Genomics Research Laboratory. This technique compares the genomes from many different people to find genetic markers associated with a particular observable characteristic or risk of disease. The goal is to understand how genes contribute to the disease and to use that understanding to help develop better prevention and treatment strategies.
NCI also funds the Cancer Genetics NetworkExit Disclaimer. This network is a resource for researchers studying inherited cancer risk, the integration of this information into medical practice, and behavioral, ethical, and public health issues associated with human genetics.
Additional NCI research is focused on improving genetic counseling methods and outcomes, the risks and benefits of at-home genetic testing, and the effects of advertising of these tests on patients, providers, and the health care system. Researchers are also working to improve the laboratory methods available for genetic testing.
Genetic Changes and Cancer
Cancer is a genetic disease—that is, cancer is caused by certain changes to genes that control the way our cells function, especially how they grow and divide. These changes include mutations in the DNA that makes up our genes.
Genetic changes that increase cancer risk can be inherited from our parents if the changes are present in germ cells, which are the reproductive cells of the body (eggs and sperm). Such changes, called germline changes, are found in every cell of the offspring.
Cancer-causing genetic changes can also be acquired during one’s lifetime, as the result of errors that occur as cells divide during a person’s lifetime or exposure to substances, such as certain chemicals in tobacco smoke, and radiation, such as ultraviolet rays from the sun, that damage DNA.
Genetic changes that occur after conception are called somatic (or acquired) changes. They can arise at any time during a person’s life. The number of cells in the body that carry such changes depends on when the changes occur during a person’s lifetime.
In general, cancer cells have more genetic changes than normal cells. But each person’s cancer has a unique combination of genetic alterations. Some of these changes may be the result of cancer, rather than the cause. As the cancer continues to grow, additional changes will occur. Even within the same tumor, cancer cells may have different genetic changes.
Hereditary Cancer Syndromes
Inherited genetic mutations play a major role in about 5 to 10 percent of all cancers. Researchers have associated mutations in specific genes with more than 50 hereditary cancer syndromes, which are disorders that may predispose individuals to developing certain cancers.
Genetic tests can tell whether a person from a family that shows signs of such a syndrome has one of these mutations. These tests can also show whether family members without obvious disease have inherited the same mutation as a family member who carries a cancer-associated mutation. (For more information, see this overview of genetic testing for hereditary cancer syndromes.)
Many experts recommend that genetic testing for cancer risk be considered when someone has a personal or family history that suggests an inherited cancer risk condition, as long as the test results can be adequately interpreted (that is, they can clearly tell whether a specific genetic change is present or absent) and when the results provide information that will help guide a person’s future medical care.
Cancers that are not caused by inherited genetic mutations can sometimes appear to “run in families.” For example, a shared environment or lifestyle, such as tobacco use, can cause similar cancers to develop among family members. However, certain patterns in a family—such as the types of cancer that develop, other non-cancer conditions that are seen, and the ages at which cancer develops—may suggest the presence of a hereditary cancer syndrome.
Even if a cancer-predisposing mutation is present in a family, not everyone who inherits the mutation will necessarily develop cancer. Several factors influence the outcome in a given person with the mutation, including the pattern of inheritance of the cancer syndrome.
Here are examples of genes that can play a role in hereditary cancer syndromes.
- The most commonly mutated gene in all cancers is TP53, which produces a protein that suppresses the growth of tumors. In addition, germline mutations in this gene can cause Li-Fraumeni syndrome, a rare, inherited disorder that leads to a higher risk of developing certain cancers.
- Inherited mutations in the BRCA1 and BRCA2 genes are associated with hereditary breast and ovarian cancer syndrome, which is a disorder marked by an increased lifetime risk of breast and ovarian cancers in women. Several other cancers have been associated with this syndrome, including pancreatic and prostate cancers, as well as male breast cancer.
- Another gene that produces a tumor suppressor protein is PTEN. Mutations in this gene are associated with Cowden syndrome, an inherited disorder that increases the risk of breast, thyroid, endometrial, and other types of cancer.
For more genes that can play a role in hereditary cancer syndromes, see Genetic Testing for Hereditary Cancer Syndromes.
Genetic Test Results
Genetic tests are usually requested by a person’s doctor or other health care provider. Genetic counseling can help people consider the risks, benefits, and limitations of genetic testing in their particular situations.
The results of genetic tests can be positive, negative, or uncertain. A genetic counselor, doctor, or other health care professional trained in genetics can help an individual or family understand their test results. These professionals can also help explain the incidental findings that a test may yield, such as a genetic risk factor for a disease that is unrelated to the reason for administering the test. And they can clarify the implications of test results for other family members.
Medical test results are normally included in a person’s medical records, particularly if a doctor or other health care provider has ordered the test or has been consulted about the test results. Therefore, people considering genetic testing should understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their insurance company or employer, if their employer provides the patient’s health insurance as a benefit.
However, legal protections are in place to prevent genetic discrimination. The Genetic Information Nondiscrimination Act of 2008 is a federal law that prohibits discrimination based on genetic information in determining health insurance eligibility or rates and suitability for employment. In addition, because a person’s genetic information is considered health information, it is covered by the Privacy Rule of the Health Information Portability and Accountability Act of 1996.
Clinical DNA Sequencing
Until recently, most genetic testing for cancer focused on testing for individual inherited mutations. But, as more efficient and cheaper DNA sequencing technologies have become available, sequencing of an individual’s entire genome or the DNA of an individual’s tumor is becoming more common.
Clinical DNA sequencing can be useful in detecting many genetic mutations at one time. Targeted multiple-gene panels test for many inherited mutations or somatic mutations at the same time. These panels can include different genes and be tailored to individual tumor types. Targeted gene panels limit the data to be analyzed and include only known genes, which makes the interpretation more straightforward than in broader approaches that assess the whole genome (or tumor genome) or significant parts of it. Multiple-gene panel tests are becoming increasingly common in genetic testing for hereditary cancer syndromes.
Tumor sequencing can identify somatic mutations that may be driving the growth of particular cancers. It can also help doctors sort out which therapies may work best against a particular tumor. For instance, patients whose lung tumors harbor certain mutations may benefit from drugs that target these particular changes.
Testing tumor DNA may reveal a mutation that has not previously been found in that tumor type. But if that mutation occurs in another tumor type and a targeted therapy has been developed for the alteration, the treatment may be effective in the “new” tumor type as well.
Tumor sequencing can also identify germline mutations. Indeed, in some cases, the genetic testing of tumors has shown that a patient’s cancer could be associated with a hereditary cancer syndrome that the family was not aware of.
As with testing for specific mutations in hereditary cancer syndromes, clinical DNA sequencing has implications that patients need to consider. For example, they may learn incidentally about the presence of germline mutations that may cause other diseases, in them or in their family members.