Genetic Testing

Definition

Genetic testing is a process which involves examining individuals' genetic material for the presence of a change that indicates why they may have developed a disease or disorder. Genetic testing may also tell patients if they are at increased risk for developing a disease such as cancer in the future, but currently do not have any symptoms of that particular disease.

Description

Genetic testing is usually done by taking a sample of a person's blood. The changes in the genetic material that can be detected by this testing vary in size. Sometimes parts or even entire chromosomes may be altered or missing completely. Other times, a mutation is present on a gene that causes it to malfunction. One type of mutation is known as a hereditary mutation. Hereditary mutations may also be called germline mutations because they are found in all the cells of a person's body, including the reproductive or germ cells, the sperm for a male and the egg for a female. This is why hereditary mutations can be inherited, or passed from a parent to a child. Genetic testing often looks for the presence or absence of these types of mutations in genes.

Genes and cancer

Cancer is defined as one cell that grows out of control and subsequently invades nearby cells and tissue. There are several steps involved in the process that causes a normal cell to become malignant (cancerous). It is believed that different genes play a role in this specialized process. Oncogenes typically promote or encourage cell growth. However, if they are overexpressed or mutated, they may cause cancer to arise. Tumor-suppressor genes, when working properly, prevent cells from growing too quickly or out of control. They are often compared to brakes in a car. If these genes cannot perform their function because of the presence of a mutation, cells may grow out of control and become cancerous. Finally, cancer may also be caused by faulty DNA repair genes. These genes usually correct the common mistakes that are made by the body as the DNA copies itself, a normally occurring process. However, if these genes can't correct mistakes, the mistakes may accumulate and lead to cancer.

It is very important to remember that while all cancer is genetic, or caused by changes in genes, just a small amount of cancer is hereditary, or passed from parent to child. It is thought that only about 5-10% of cancer falls into this category. Therefore, the majority of cancer is not hereditary. Most cancer is due to other causes, such as environmental exposures. Usually it is very difficult to determine the exact cause of cancer that is not known to be the result of an altered gene.

Identifying at-risk individuals and families for hereditary cancer

Although scientists have identified genetic tests for common cancers, like breast and colon cancer, genetic testing is not an option that should be offered to all people with cancer, or even to those who may have cancer in their family. This is primarily due to the fact that most cancer does not run in families. Therefore, genetic testing will not be helpful for many people. In order to determine those who may benefit from undergoing genetic testing for cancer, health care providers need to be aware of certain aspects of an individual's personal and family history of cancer.

A person who is thinking about having a genetic test for cancer often meets with a genetic counselor, a specially trained health care provider. When a patient meets with a genetic counselor, the counselor will ask the patient about their personal and family history of cancer. The counselor will also draw a very detailed family tree, also known as a pedigree. The counselor will then examine the family tree to determine if there are certain "clues" that the cancer may be hereditary.

The clues that may be observed in a family tree are listed below, with breast cancer used as an example.

• Multiple relatives in more than one generation with the same type of cancer, or related cancers. For example, a grandmother, mother and daughter with breast cancer. Or, relatives with both breast and ovarian cancer.
• Cancer occurring in the family at younger ages than is typically observed in the general population. For example, breast cancer usually occurs in women as they get older, most commonly in their 60's to 70's. However, in families that may have an alteration in a gene increasing their risk for developing breast cancer, the disease may occur in women at much younger ages.
• Cancer that occurs in paired organs. For example, breast cancer that occurs in both of a woman's breasts. This is also called bilateral breast cancer.
• Development of more than one type of related cancer in the same person within a family. For example, a female relative with both breast and ovarian cancer diagnosed at young ages.
• Specific ethnic background. Mutations in certain cancer susceptibility genes may be more likely to occur in individuals of specific ethnic backgrounds. For this reason, it is very important that a complete family tree includes the country where a person's relatives originally lived.

If a genetic counselor or other health care provider observes one or more of the above features in an individual's family tree, he or she may talk about the option of genetic testing with the patient. In the case of cancer genetic testing, it is only offered to a patient if there are options available to screen for the certain cancer and detect it early, or to possibly prevent it from occurring at all.

The process of genetic testing

The process of genetic testing for genes that may increase risk for cancer is different from other medical tests. Genes involved in cancer are called cancer susceptibility genes. If a mutation is identified in one of these genes, it does not reveal that a person has cancer, but rather whether an individual has an increased risk to develop cancer in the future. In addition, if the person undergoing genetic testing has already had cancer, genetic testing may tell them whether they are at increased risk for developing cancer again. However, the risk for developing cancer is not 100%. The likelihood that a person will develop cancer if they carry an altered gene is called penetrance. Penetrance may differ even among relatives in the same family, and the reasons are not well understood. For example, a mother with a mutation in a cancer susceptibility gene may never develop cancer, but may pass this mutation on to her daughter, who is then diagnosed with cancer at a young age.

For a family in which an inherited mutation has not been previously identified, it is best to begin genetic testing by obtaining a blood sample from a person who has had cancer at a young age. From this blood sample, scientists will be able to extract some DNA. There are a number of different ways that they can then look at the DNA to determine if a mutation is present. The most common is known as sequencing, whereby the chemical sequence of a patient's DNA is compared to DNA that is known to be normal. Scientists will look for any differences, such as missing or extra pieces of DNA in the patient's gene.

Testing can be very expensive and it may take several weeks or months to obtain results. Also, insurance companies will sometimes not cover the cost of testing. Some families are able to participate in research studies where genetic counseling and testing is offered at a lower cost or free of charge.

Categories of results

A positive result indicates the presence of a genetic mutation that is known to be associated with an increased risk for developing cancer. Once this kind of mutation has been found in an individual, it is possible to test this person's relatives, like their children, for the presence or absence of that particular mutation. This testing can be done in a relatively short period of time and provides results that are clearly positive or negative for a particular mutation.

If a relative in a family is tested for a mutation in a cancer susceptibility gene that was previously identified in their family, and they are not found to have this mutation, this type of test result is called a true negative. This means that they did not inherit the mutation in the gene that is the reason why their relative (s)developed cancer. If a person receives a true negative test result, their risk for developing cancer is generally considered to be reduced to that of someone in the general population. Also, because they did not inherit the mutation, they cannot pass it down to any of their children. The term true negative is used to distinguish this test result from a negative or indeterminate result, which is described below.

If the first person tested within a family is not found to have an alteration in a cancer susceptibility gene, this result is negative. However, this result is often called indeterminate. This is because a negative test result cannot completely rule out the possibility of hereditary cancer still being present within a family. The interpretation of this type of result can be very complex. For example, a negative result may mean that the method used to detect mutations may not be sensitive enough to identify all mutations in the gene, or perhaps the mutation is in a part of the gene that is difficult to analyze. It may also mean that a person has a mutation in another cancer susceptibility gene that has not yet been discovered or is very rare. Finally, a negative result could mean that the person tested does not have an increased risk for developing cancer because of a mutation in a single cancer susceptibility gene.

Finally, sometimes mutations are identified in cancer genes and scientists do not know what they mean. They do not know if these types of mutations affect the functioning of the gene and thereby increase a person's risk for cancer, or if they are normal changes in the DNA that just make one person's gene a little bit different from another person's. When this occurs, the genetic counselor may work with the laboratory to determine if future research can be done to find out the meaning of the patient's test result.

In general, a genetic counselor will help a patient to understand the meaning of his or her genetic test result, whether positive, negative, or indeterminate.

Benefits and limitations of undergoing genetic testing for cancer susceptibility genes

There are potential benefits for patients who undergo genetic testing, but there are also possible limitations and risks regarding the information that is obtained. A genetic counselor will discuss these issues in detail with a patient. Before undergoing genetic testing, a patient will also sign a consent form. This is a written agreement indicating that the patient understands the benefits and risks of genetic testing and has made an independent decision to undergo the testing. The informed consent process is a very important part of genetic counseling and testing. With the exception of FAP, where polyps and subsequently colon cancer can occur at young ages or in the teens, the cancers associated with carrying an altered breast or colon cancer susceptibility gene do not typically occur at very young ages. Therefore, genetic testing for mutations in these genes is usually only offered to those men and women who are 18 years of age or older. In addition, individuals who are 18 or older are considered legally able to provide informed consent.

Benefits of participating in genetic testing for alterations in cancer susceptibility genes:

• Results of genetic testing may provide additional information about the increased risk for developing cancer in the future. It may also provide relief from anxiety if a person learns that they do not carry an altered gene.
• If a person finds out that they are at increased risk for developing cancer, they may choose to be screened for this cancer at a younger age and more often than someone without an altered cancer susceptibility gene. Results may also help men and women decide about prophylactic surgery.
• Testing may provide information about cancer risks for children, brothers and sisters, and other relatives.
• Genetic testing may help a person understand why they and/or their family members developed cancer. This may relieve a person from the emotional burden surrounding their cancer diagnosis.

Limitations and risks of participating in genetic testing for cancer susceptibility genes:

• It is possible that the results of genetic testing may be difficult to interpret. Even if a patient receives a positive test result, this does not mean that he/she will definitely develop cancer.
• During the process of undergoing genetic testing, a person may learn information about themselves or their family members. For example, they may learn about an adoption or that an individual is not the biological father of a child. This kind of information may cause strained relationships among relatives.
• Some patients may become sad, angry or anxious if they learn that they have a mutation in a cancer susceptibility gene. If these feelings are very intense, psychological counseling may be helpful.
• Results of genetic testing may place a person at risk for discrimination by health or life insurers, or their employer. There are some laws in effect that provide limited protection to people who undergo genetic testing. The completion of the Human Genome Project, which has mapped all the genes in the human body, will increase the number of genetic tests that are available. Therefore, additional laws need to be passed to completely protect all people who undergo genetic testing from any type of discrimination.

Genes and cancer types

As of 2001, genes have been discovered that are associated with or responsible for several types of cancer, including Chronic myelocytic leukemia, Burkitt's lymphoma, retinoblastoma, Wilms' tumor, and breast and colon cancers. The remainder of this entry will focus only on genetic testing for two of the most common cancers, breast and colon cancer.

Breast cancer genetic testing

Breast and ovarian cancer statistics

All women have a risk for developing breast and ovarian cancer during their lifetime. While breast cancer is a common cancer among women in the United States, ovarian cancer is not. Most women are diagnosed with breast or ovarian cancer after the age of 50, and the great majority of cases are not hereditary. But, of the 5-10% of breast and ovarian cancer that does run in families, most is due to mutations in two genes, the BReast CAncer-1 gene (BRCA1) and the BReast CAncer-2 gene (BRCA2). The BRCA1 gene is located on chromosome 17, and was discovered in 1994. The BRCA2 gene is on chromosome 13, and was discovered in 1995.

BRCA1 and BRCA2 genes

BRCA1 and BRCA2 genes are tumor suppressor genes and are inherited in a dominant fashion. This means that children of a parent with a mutation in one of the breast cancer genes have a 50% chance to inherit this mutation. These mutations can be passed from either mother or father, and can be inherited by both males and females. The mutations may be detected by performing genetic testing on a patient's blood sample.

Mutations in these genes are more common in people who are Ashkenazi (Eastern or Central European) Jewish. While these mutations may be more common in this specific population, they can be identified in a person of any ethnic background.

Cancer risks

Females who inherit a mutation in the BRCA1 or the BRCA2 gene have an increased risk for developing breast and/or ovarian cancer over their lifetime. The lifetime risk for breast cancer may be as high as 85%, as compared to about 13% in the general population. The lifetime risk for developing ovarian cancer may be as high as 60%, as compared to 1.5% in the general population. Males who inherit a mutation in one of these genes are also at increased risk for developing certain cancers, including prostate, colon and breast cancer.

Men and women who inherit an alteration in the BRCA2 gene also have an increased risk to develop more rare cancers, such as pancreatic and stomach cancer. However, these risks are much lower than those observed for breast, ovarian, and prostate cancer.

Screening and prevention options

It is recommended that individuals who are at increased risk for developing breast cancer undergo increased surveillance. This means that they may choose to see their physicians for medical screening tests at an earlier age and more often than they would if they did not have an altered gene. For example, it is recommended that women with an altered BRCA1 or BRCA2 gene undergo mammograms at a younger age than is recommended in the general population. It is also recommended that these women see their doctors more often to do a breast exam and also perform breast self-exams regularly. Because women who have a mutation in BRCA1 or BRCA2 are also at increased risk for developing ovarian cancer, they may also choose to be screened closely for this cancer. This screening involves undergoing a test, called a CA-125, which looks for protein levels in a woman's blood. Women may also undergo a pelvic ultrasound to look at the size and shape of the ovaries to determine if cancer may be growing in that area. It is important to mention that ovarian cancer is a difficult cancer to detect, and these screening methods may not be able to find the cancer at an early stage when a woman can undergo successful treatment.

Men with an altered BRCA1 or BRCA2 gene may also choose to be screened earlier and more frequently for the cancers they are at increased risk to develop. Prostate screening consists of a test called prostate specific antigen (PSA) that looks for protein levels in a man's blood. Men may also undergo an examination by a physician. There are no standard screening recommendations for males who are at increased risk for breast cancer. It is usually recommended that they learn to do breast self-exams and talk with their doctors if they find any changes in their breast tissue.

Some women at increased risk for developing breast or ovarian cancer may decide to have prophylactic or preventive surgery. This means that they may choose to have their healthy breasts or ovaries removed before cancer develops. However, even the very best surgeon cannot remove all of the breast or ovarian tissue. Therefore, even if a woman has her breasts or ovaries removed preventively, she may still develop cancer in the remaining tissue, but this risk is believed to be small.

Finally, some healthy women who are at increased risk for breast or ovarian cancer may decide to take certain medications that have been shown to reduce risk. As some of these medications have been studied only in the general population, further research is underway to find out how effective these medications are for women with an inherited risk for developing cancer.

Colon cancer genetic testing

Colon cancer statistics

Males and females in the general population have a 6% risk for developing colon cancer over their lifetime, and the average individual is diagnosed in their 60s to 70s. Similar to breast and ovarian cancer, most colon cancer does not run in families. However, some colon cancer is hereditary, and may be due to a mutation in a colon cancer susceptibility gene. Three of the more common hereditary colon cancer syndromes are described below.

Familial Adenomatous Polyposis (FAP)

FAP is a syndrome in which individuals develop numerous polyps (growths) in their colon or rectum. This disorder may also be called familial polyposis or Gardner's syndrome. Males or females with FAP often have hundreds of precancerous polyps at young ages, such as when they are teenagers or young adults.

FAP is due to a mutation in a gene called APC. Mutations in this gene are dominantly inherited. In about 80% of families genetic testing performed on a blood sample can find the alteration in the APC gene that is causing this disorder. It is believed that 2/3 of the people with FAP have inherited a mutated gene from their parent. The other 1/3 of individuals with FAP are believed to be new (sporadic) mutations, meaning that the alteration in the APC gene was not inherited from a parent. Individuals with sporadic mutations can pass the mutation on to their children.

Cancer risks

Due to the fact that individuals with FAP develop so many polyps in their colon, there is a very high risk that these polyps, if not removed, will develop into colon cancer. Individuals with FAP may also develop precancerous polyps in other organs, such as their stomach or small intestine. Young people with FAP may also be at increased risk for developing a tumor in the liver, known as a hepatoblastoma. They are also at increased risk for developing tumors in other parts of the body, such as the thyroid gland or pancreas. Males or females with FAP may also have other manifestations of the disease. For example, they may have cysts or bumps on their skin or on the bones of their legs or arms, or freckle-like spots in their eyes.

APC I1307K mutation

In 1997 scientists identified another mutation on the APC gene, known as I1307K. This mutation is found only in individuals who are of Ashkenazi Jewish descent. It is estimated that about 6% of individuals who are Jewish have this particular mutation. The I1307K mutation itself does not cause an increased risk for colon cancer, but rather makes the APC gene more likely to undergo other genetic changes. These other genetic changes increase a person's risk for developing colon cancer. Genetic testing can be performed on a blood sample to determine if an individual carries the I1307K mutation. A person with this mutation has a 50% chance of passing it on to his/her children.

Cancer risks

Individuals who carry the I1307K mutation have an 18%-30% risk for developing colon cancer over their lifetime. Research is ongoing to determine if individuals with this mutation may also be at risk for developing other types of cancer, such as breast cancer.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

HNPCC, also known as Lynch Syndrome, is a condition in which individuals have an increased risk for developing colon cancer, even if there are very few or no polyps present in the colon. It is believed that mutations in one of five cancer susceptibility genes are associated with most cases of HNPCC. These genes are known as hMSH2, hPMS1, MSH6 (all on chromosome 2), hMLH1 (chromosome 1) and hPMS2 (chromosome 7). It is possible that other genes may be found which are also associated with HNPCC. Mutations in these genes are dominantly inherited, and may be able to be detected through genetic testing performed on a patient's blood sample.

Cancer risks

Individuals with an altered HNPCC gene have a much higher risk for developing colon cancer, often at a younger age (less than 50) than people in the general population. Those with an HNPCC mutation are at increased risk for developing other types of cancer, including stomach, urinary tract, bile duct, uterine and ovarian cancer. It is recommended that men and women also be screened closely for these cancers.

Screening and prevention options

It is recommended that all individuals who are at increased risk for developing colon cancer undergo screening for this cancer. Screening for colon cancer consists of two main types of tests. The first test is called a sigmoidoscopy. It is performed by inserting a flexible tube, called a sigmoidoscope into the anus to look at the rectum and the lower colon. The doctor can use the scope to see whether polyps may be present, but these growths can not be removed with this test. The second test is known as a colonoscopy. While it is very similar to a sigmoidoscopy, it allows a doctor to see the entire colon. Also, with the use of a colonoscope a polyp can be easily removed at the same time a person is undergoing the test. However, because a colonoscopy is a more invasive test, patients have to be sedated. For patients who are at increased risk for developing colon cancer, it is recommended that they undergo this screening at younger ages and more often then individuals in the general population. For example, because cancer can occur at such young ages for individuals with FAP, it is recommended that they have a sigmoidoscopy beginning at age 11.

Finally, men and women with a mutation in a colon cancer susceptibility gene may take certain medications that have been approved for use in individuals with an increased risk for developing colon cancer.

The only way to prevent colon cancer from developing is to remove the colon entirely. If a person with FAP, HNPCC or the I1307K mutation develops colon cancer he/she may choose to have the colon removed. In addition, if an individual is very anxious about developing colon cancer he or she may choose to have the colon removed before cancer develops. There are several different procedures for removing the colon that allow a person to function normally. Women with an HNPCC mutation may also consider prophylactic removal of their ovaries and uterus.

See Also Cancer genetics; Familial cancer syndromes

Resources

BOOKS

Offitt, Kenneth, M.D., M.P.H., Clinical Cancer Genetics. New York:Wiley Liss Inc., 1998.

PERIODICALS

Burke, W., et al. "Recommendations for Follow-up Care of Individuals With an Inherited Predisposition to Cancer-Hereditary Nonpolyposis Colon Cancer." Journal of the American Medical Association 277 (March 1997): 915-19.

Burke, W., et al. "Recommendations for Follow-up Care of Individuals With an Inherited Predisposition to Cancer-BRCA1 and BRCA2." Journal of the American Medical Association 277 (March 1997): 997-03.

Cummings, S., and O. Olopade. "Predisposition Testing for Inherited Breast Cancer." Oncology 12 (August 1998): 1227-41.

Laken, S.J., et al. "Familial Colorectal Cancer in Ashkenazim due to a hymermutable tract in APC." Nature Genetics 17 (1997): 79-83.

Lindor, N.M., et al. "The Concise Handbook of Family Cancer Syndromes." Journal of the National Cancer Institute 90 (July 1998): 1039-71.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Road, NE, Atlanta, GA30329. (800)ACS-2345.<http://www.cancer.org>.

National Cancer Institute. 31 Center Drive, MSC 2580 Bethesda, MD 20892-2580. (800)4-CANCER.<http://www.nci.nih.gov>.

National Society of Genetic Counselors. 233 Canterbury Drive, Wallingford, PA 19086-6617. (610) 872-7608. <http://www.nsgc.og>.

OTHER

Johns Hopkins Hereditary Colorectal Cancer Resources. 23March 2001 <http://www.hopkins-coloncancer.org/>.

Genetic Health. 27 March 2001 <http://www.genetichealth.com/>.

Tiffani A. DeMarco, M.S.

Cancer

—The process by which cells grow out of control and subsequently invade nearby cells and tissue.

Cancer susceptibility gene

—The type of genes involved in cancer. If a mutation is identified in this type of gene it does not reveal whether or not a person has cancer, but rather whether an individual has an increased risk (is susceptible) to develop cancer (or develop cancer again) in the future.

Colonoscopy

—A screening test performed with a tube called a colonoscope that allows a doctor to view a patient's entire colon and rectum.

Chromosome

—Structures found in the center of a human cell on which genes are located.

DNA repair genes

—A type of gene that usually corrects the common mistakes that are made by the body as DNA copies itself. If these genes are mutated and cannot correct these mistakes they may accumulate and lead to cancer.

Gene

—Packages of DNA that control the growth, development and normal function of the body.

Genetic counselor

—A specially trained health care provider who helps individuals understand if a disease (such as cancer)is running in their family and their risk for inheriting this disease. Genetic counselors also discuss the benefits, risks and limitations of genetic testing with patients.

Hepatoblastoma

—A cancerous tumor of the liver. Individuals with FAP have an increased risk for developing this type of tumor at a young age.

Mammogram

—A screening test that uses X-rays to look at a woman's breasts for any abnormalities, such as cancer.

Mutation

—An alteration in the number or order of the DNA sequence of a gene.

Oncogene

—Genes that typically promote cell growth. If mutated, they may encourage cancer to develop.

Pedigree

—A family tree. Often used by a genetic counselor to determine if a disease may be passed from a parent to a child.

Penetrance

—The likelihood that a person will develop a disease (such as cancer), if they have a mutation in a gene that increases their risk for developing that disorder.

Polyp

—A growth that may develop in the colon. These growths may be benign or cancerous.

Prophylactic surgery

—The preventive removal of an organ or tissue before a disease such as cancer develops.

Sequencing

—A method of performing genetic testing where the chemical order of a patient's DNA is compared to that of normal DNA.

Sigmoidoscopy

—A screening test performed with a flexible scope called a sigmoidoscope, that allows a doctor to view a limited portion of a patient's colon or rectum for the presence of polyps.

Tumor suppressor gene

—Genes that typically prevent cells from growing out of control and forming tumors that may be cancerous.

QUESTIONS TO ASK THE DOCTOR

• What is the likelihood that the cancer in my family is due to a mutation in a cancer susceptibility gene?
• If the cancer in my family is hereditary, what is the chance that I carry a mutation in a cancer susceptibility gene?
• What are the benefits, limitations and risks of undergoing genetic testing?
• What is the cost of genetic testing and how long will it take to obtain results?
• If I undergo genetic testing, will my insurance company pay for testing? If so, will I want to share my results with them?
• What does a positive test result mean for me?
• What does a negative test result mean for me?
• If I test positive for a mutation in a cancer susceptibility gene, what are the best options available for screening and prevention? What research studies may I be eligible to participate in?
• What legislation is in effect to protect me against discrimination by my insurer or employer?