Genetic testing

Definition

A genetic test examines the genetic information contained inside a person's cells, called DNA, to determine if that person has or will develop a certain disease or could pass a disease to his or her offspring. Genetic tests also determine whether or not couples are at a higher risk than the general population for having a child affected with a genetic disorder.

Description

Deoxyribonucleic acid (DNA) is a long molecule made up of two strands of genetic material coiled around each other in a unique double helix structure. This structure was discovered in 1953 by Francis Crick and James Watson.

DNA is found in the nucleus, or center, of most cells (Some cells, such as a red blood cell, don't have a nucleus). Each person's DNA is a unique blueprint, giving instructions for a person's physical traits, such as eye color, hair texture, height, and susceptibility to disease. DNA is organized into structures called chromosomes.

The instructions are contained in DNA's long strands as a code spelled out by pairs of bases, which are four chemicals that make up DNA. The bases occur as pairs because a base on one strand lines up with and is bound to a corresponding base on the other strand. The order of these bases form DNA's code. The order of the bases on a DNA strand is important to ensuring that we are not affected with any genetic diseases. When the bases are out of order, or missing, then often times, our cells do not produce important proteins which can lead to a genetic disorder. While our genes are found in every cell of our body, not every gene is functioning all of the time. Some genes are turned on during critical points in development and then remain silent for the rest of our lives. While other genes remain active all of our lives so that our cells can produce important proteins that help us digest food properly or fight off the common cold.

The specific order of the base pairs on a strand of DNA is important in order for the correct protein to be produced. A grouping of three base pairs on the DNA strand is called a codon. Each codon, or three base pairs, comes together to spell a word. A string of many codons together can be thought of as a series of words all coming together to make a sentence. This sentence is what instructs our cells to make a protein that helps our bodies function properly.

Our DNA strands containing a hundred to several thousand copies of genes are found on structures called chromosomes. Each cell typically has 46 chromosomes arranged into 23 pairs. Each parent contributes one chromosome to each pair. The first 22 pairs are called autosomal chromosomes, or non-sex chromosomes and are assigned a number from 1–22. The last pair are the sex chromosomes and include the X and the Y chromosomes. If a child receives an X chromosome from each parent, the child is female. If a child receives an X from the mother, and a Y from the father, the child is male.

Just as each parent contributes one chromosome to each pair, so each parent contributes one gene from each chromosome. The pair of genes produces a specific trait in the child. In autosomal dominant conditions, it takes only one copy of a gene to influence a specific trait. The stronger gene is called dominant; the weaker gene, recessive. Two copies of a recessive gene are needed to control a trait while only one copy of a dominant gene is needed. Our sex chromosomes, the X and the Y also contain important genes. Some genetic diseases are caused by missing, or altered genes on one of the sex chromosomes. Males are most often affected by sex chromosome diseases when they inherit an X chromosome with missing or mutated genes from their mother.

TYPES OF GENETIC MUTATIONS. Genetic disease results from a change, or mutation, in a chromosome or in one or several base pairs on a gene. Some of us inherit these mutations from our parents, called hereditary or germline mutations, while other mutations can occur spontaneously, or for the first time in an affected child. For many of the adult on-set diseases, genetic mutations

can occur over the lifetime of the individual. This is called acquired or somatic mutations and these occur while the cells are making copies of themselves or dividing in two. There may be some environmental effects, such as radiation or other chemicals, which can contribute to these types of mutations as well.

There are a variety of different types of mutations that can occur in our genetic code to cause a disease. And for each genetic disease, there may be more than one type of mutation to cause the disease. For some genetic diseases, the same mutation occurs in every individual affected with the disease. For example, the most common form of dwarfism, called achondroplasia, occurs because of a single base pair substitution. This same mutation occurs in all individuals affected with the disease. Other genetic diseases are caused by different types of genetic mutations that may occur anywhere along the length of a gene. For example, cystic fibrosis, the most common genetic disease in the caucasian population is caused by over hundreds of different mutations along the gene. Individual families may carry the same mutation as each other, but not as the rest of the population affected with the same genetic disease.

Some genetic diseases occur as a result of a larger mutation which can occur when the chromosome itself is either rearranged or altered or when a baby is born with more than the expected number of chromosomes. There are only a few types of chromosome rearrangements which are possibly hereditary, or passed on from the mother or the father. The majority of chromosome alterations where the baby is born with too many chromosomes or missing a chromosome, occurs sporadically or for the first time with a new baby.

The type of mutation that causes a genetic disease will determine the type of genetic test to be performed. In some situations, more than one type of genetic test will be performed to arrive at a diagnosis. The cost of genetic tests vary: chromosome studies can cost hundreds of dollars and certain gene studies, thousands. Insurance coverage also varies with the company and the policy. It may take several days or several weeks to complete a test. Research testing where the exact location of a gene has not yet been identified, can take several months to years for results.

— Katherine S. Hunt, MS

Key Terms: Cancer, Cancer susceptibility gene, Colonoscopy, Chromosome, DNA repair genes, Gene, Genetic counselor, Hepatoblastoma, Mammogram, Mutation, Oncogene, Pedigree, Penetrance, Polyp, Prophylactic surgery, Sequencing, Sigmoidoscopy.

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 or 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.

Questions to Ask the Doctor or a Genetic Counselor

• 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?

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.

Resources

Organizations

American Cancer Society. 1599 Clifton Road, NE, Atlanta, GA 30329. (800)ACS-2345. .

National Cancer Institute. 31 Center Drive, MSC 2580 Bethesda, MD 20892-2580. (800)4-CANCER. .

National Society of Genetic Counselors. 233 Canterbury Drive, Wallingford, PA 19086-6617. (610) 872-7608. .

Other

Genetic Health. [cited March 27, 2001]. .

Johns Hopkins Hereditary Colorectal Cancer Resources. [cited March 23, 2001]. .

—Tiffani A. DeMarco, M.S.

Genetic testing is now possible, as both the structure of DNA is known and methods to determine the sequence have been developed. Genetic testing brings with it benefits of diagnosis and treatment, but raises many other issues, both sociological and ethical. It is known that a great number of diseases have a genetic input; in some instances, such as single gene diseases, the genetic mutation is the sole cause of the disease. In polygenic diseases there are a number of mutations in different genes, none of which individually may have any measurable effect, but which in combination one with another may increase the likelihood that a complex disease condition, such as high blood pressure, will result.

What is genetic testing, what does it involve, and how is it done? We all have 22 pairs of chromosomes, one of each pair from each parent plus an X and Y chromosome in the male and two X chromosomes in the female. Paired genes are arrayed along the length of each pair of chromosome. Thus we all have two copies of each gene, one from each parent, plus either an X and a Y or two X chromosomes. Suppose the particular gene on a particular chromosome carries a defect responsible for a disease, while the other gene on the paired chromosome is normal, yet the person has the disease. Then the mutant gene is said to be dominant. If no disease is present then the gene is recessive; the person is a carrier, but may pass on the defective gene to the offspring. It is important to know in genetic testing whether an individual has two normal genes or one normal and one abnormal gene. Some genetic diseases are associated with X and Y chromosomes and are described as sex-linked, while genetic diseases due to gene defects on the non-sex chromosomes are called autosomal; i.e. these can affect males and females alike. Genetic testing therefore consists of looking for the gene mutation, together with the normal gene in a DNA sample, from a patient. Providing a sample is very easy; for example, simply lightly brushing the inside of the mouth yields enough cells to examine the DNA. Techniques are available to amplify (copy) the DNA in the sample, and, since the sequence of the gene involved is known, probes are used to look for the presence of normal and mutant genes. If only one type of gene is found then the sample is from a homozygous individual, who may have two normal or two abnormal genes. If both types of gene are found then the individual is heterozygous, that is they have one normal and one abnormal gene. Given this information, the consequences for the offspring follow clearly defined genetic rules. Examples of dominant inherited disorders are Huntington's chorea and retinoblastoma; of recessive disorders are cystic fibrosis (CF), sickle cell anaemia, and thalassaemia; and of sex-linked inherited disorders are haemophilia and muscular dystrophy.

Consider an example. A perfectly healthy pregnant female is offered a genetic test and discovers that she is a carrier of CF. It is most important that confidentiality is maintained and that the patient is not made to feel somehow responsible. If the father is also a carrier then the chances are 1 in 4 that the child will have CF. The chances that the child will also be a carrier, like the parents, is 50%, and the chance that the child inherits a normal gene from both parents is again 1 in 4. Testing the father involves some delay and, of course, concern for the parents. In some instances the father will be unknown or parentage of the child may be in doubt, raising further embarrassments for those involved. If the father cannot be found or refuses to take part it is possible to test the fetus by amniocentesis. In this procedure a small volume of fluid is drawn from around the foetus. This contains sufficient fetal cells to collect the DNA. If, when all the tests are done, the unborn child is found to have CF, then termination may be offered, again an ethical problem which the originally unsuspecting parents had never envisaged. Counselling is very important at this stage.

Looking to the future, it is possible that babies will be genotyped at birth and that this may allow prediction of diseases that might arise in later life. In this way prophylactic measures taken early may be able to prevent the disease appearing, or delay its onset. Furthermore, if the disease does develop, knowledge of the genetic profile will allow the most appropriate drug regimens to be prescribed. This sort of benefit will be most useful for polygenic diseases, such as high blood pressure, various forms of cancer, and asthma. It must be remembered, however, that complex diseases of this type have causes that are due both to nature and nurture. Clearly, much disease prevention can be achieved by appropriate attention to nurture — lifestyle, diet, and the like.

— Alan W. Cuthbert

Genetic testing involves examining a person's DNA in order to find changes or mutations that might put an individual, or that individual's children, at risk for a genetic disorder. These changes might be at the chromosomal level, involving extra, missing, or rearranged chromosome material. Or the changes might be extremely small, affecting just one or more of the chemical bases that make up the DNA. In a broader sense, genetic testing includes other types of testing that provide information about a person's genetic makeup, such as enzyme testing to diagnose or identify carriers for a genetic condition such as Tay-Sachs disease.

With hundreds of genetic tests available, determining who should be offered testing and under what circumstances testing should occur is relatively complicated. In general, testing is offered to those at highest risk based on their ethnic background, family history, or symptoms. However, just because genetic testing is possible and a person is at risk, this does not mean it should be offered or will be useful to that person. Genetic testing is unlike other medical tests in that individual results may also provide information about relatives, may be able to predict the likelihood of a future illness for which treatment may or may not be available, may put the person at risk for harm such as discrimination, or may have limited accuracy. There are a number of settings in which genetic testing occurs and within each setting there are a variety of indications and considerations for testing.

Prenatal Genetic Testing

Prenatal (before birth) genetic testing refers to testing the fetus for a potential genetic condition. The pregnant woman is considered the patient and makes decisions regarding prenatal testing. There are a variety of circumstances under which a woman might be offered prenatal genetic testing. The parents of the fetus may have a genetic disorder, or they may be what is known as carriers. An abnormality or birth defect may be detected on ultra-sound that could indicate a genetic condition. The fetus may be identified to be at increased risk for a chromosome abnormality, such as Down syndrome, or a birth defect, such as spina bifida, based on the result of a maternal serum screening test performed on the mother. This is a test that looks at several proteins made by the fetus that are found in a woman's bloodstream while she is pregnant. Or, the mother might be at increased risk for having a baby with a chromosome abnormality because of her age. While all women are at risk for having a baby with a chromosome abnormality, women who are age thirty-five or older are offered prenatal chromosome testing because the chance their fetus has a chromosome abnormality is equal to or higher than the chance she will have a miscarriage due to the sampling procedure.

As with most genetic testing, prenatal genetic testing should occur in conjunction with genetic counseling. The genetic counselor provides supportive, nondirective counseling and information. Nondirective counseling means that while the counselor will try to facilitate decisions regarding testing and future pregnancy management, she will not make specific recommendations. Because the decision to undergo testing is personal and must take into account differences in beliefs, life circumstances, and the risk of the procedure, the decisions regarding testing and pregnancy management must be made by the patient. This encounter is also likely to include information about risk of the fetus being affected, the disorder in question, and available testing options.

Most genetic tests are performed on tissue or a blood sample. For obvious reasons, obtaining a sample from a fetus is not the same as obtaining one from a child or adult. Prenatal testing procedures are invasive, and there is a risk of miscarriage with every procedure. For this reason, specially trained physicians perform these tests. Prenatal testing can be accomplished using three different methods: amniocentesis, chorionic villus sampling, and percutaneous umbilical blood sampling. These tests differ in the type of fetal tissue studied, the timing of the testing during pregnancy, and in their risks and benefits.

Amniocentesis is the most common, and it carries the lowest risk of miscarriage (about one in two hundred pregnancies). It is typically performed between sixteen and eighteen weeks into the pregnancy and involves collecting a small amount of amniotic fluid that contains cells of the developing fetus, which can be used for testing. Chorionic villus sampling is performed earlier than amniocentesis, typically between ten and twelve weeks of pregnancy, but about one in one hundred pregnancies are miscarried as a result of this procedure. It involves obtaining a small sample of chorionic villi (fingerlike projections of the chorion, a membrane that will later develop into the placenta), which should contain cells of the fetus. Percutaneous umbilical blood sampling, typically performed after eighteen weeks, is the most difficult to perform and carries the highest risk of miscarriage (about one in fifty pregnancies). It involves withdrawing blood from the umbilical cord and is primarily used when results are needed extremely quickly, or when only a fetal blood sample can provide a given answer about the fetus. For example, it may be used to test the fetus if the mother has been exposed to an infectious organism known to cause birth defects.

Assisted Reproduction

While in vitro fertilization has been available for over two decades, more recently it has become possible to test the resulting embryos for genetic disorders when the embryos are between eight and sixteen cells in size. In this procedure, one to two cells are removed, and the section of DNA containing the gene in question is replicated and tested. Only those embryos identified to be free of risk (based on the DNA results) for developing the genetic disorder are implanted in the uterus. This technique is not widely available, however, and it is both expensive and time consuming. Thus, it is used only infrequently.

Newborn Screening

Newborn screening is unique in being the only genetic testing that it is mandated by the state. The premise of newborn screening is that, for some disorders very early detection and initiation of treatment will prevent health problems, often mental retardation. All newborn infants are tested for a variety of genetic disorders. Each state determines for itself for what disorders to test their newborns. Disorders are chosen based on severity, incidence, ease and accuracy of testing, cost, and benefit of early diagnosis. All states test newborns for phenylketonuria (PKU), a metabolic disorder that is almost never evident at birth. Individuals with PKU are missing an enzyme called phenylalanine hydroxylase, which results in the buildup of phenylalanine. If left untreated, severe mental retardation develops. However, infants with PKU who are placed on a diet low in phenylalanine immediately after birth are expected to develop normally, making PKU an excellent candidate for newborn screening.

Symptomatic Genetic Testing

Genetic testing of individuals who are exhibiting symptoms of a genetic disorder is relatively straightforward. Testing is necessary to either make or confirm a diagnosis, which may improve treatment and establish risk estimates for other family members.

A concern related to symptomatic testing is the duty to recontact the patient in the future if more information becomes available. Often, symptomatic individuals, usually children, present with a variety of symptoms for which no diagnosis can be made clinically and for which there is no genetic test. However, with the completion of the Human Genome Project and the wealth of research being conducted, new genes are discovered regularly, which may result in new testing possibilities. Most physicians inform their patients that more information may be available in the future and ask their patients to contact the clinic periodically to inquire about such updates. It is unclear whether this is sufficient to fulfill the physicians' obligation; however, no clear standards exist on this issue.

Carrier Testing

Another common testing situation is carrier testing for autosomal recessive disorders. Autosomal recessive disorders are caused by the inheritance of two nonfunctioning genes, one from each carrier parent. The parents are referred to as carriers because they carry only one nonfunctioning gene and are, therefore, not affected by the disorder. Every individual is thought to be an unaffected carrier of some autosomal recessive disorder. This is only a problem, however, if two individuals who both carry the same recessive disorder conceive a child together. Under this circumstance, the child would have a one in four (25%) chance of inheriting a nonworking copy from each parent, thereby inheriting the disorder.

There are hundreds of genetic tests available, but it is not practical to perform every available test on each person. Carrier testing is typically offered only to those individuals who are at increased risk based on family history or ethnic background. While family history bears an obvious correlation, ethnic background is important because those who descend from the same group of ancestors are more likely to carry the same genetic changes. For example, individuals of Ashkenazi Jewish descent have about a one in thirty chance of being a carrier for a condition called Tay-Sachs disease, whereas the carrier frequency is only about one in 300 in other populations. In instances such as this, population screening is often recommended.

Presymptomatic Testing

Presymptomatic testing (that is, testing a healthy person before symptoms appear) may be considered for a genetic disorder for which there is a family history. The decision to undergo this type of testing is not usually straightforward and should always be accompanied by genetic counseling. There are a number of considerations to take into account when deciding whether to proceed with testing. The first is the usefulness of the information. How will knowing the genetic information benefit the person? Testing is more favorable when preventive treatment is available, when results might have a significant impact upon life decisions, such as having children or getting married, or if it will ease extreme anxiety to learn one's genetic status. If no treatment is available, as in the case of Huntington's disease and other triplet repeat diseases, the information may be of less benefit. In some cases it may even be psychologically harmful.

The second consideration is accuracy, not only of the actual test result, but also of its ability to predict the development of the disorder. Some disorders are caused by more than one gene, or by multiple changes or mutations in the same gene. A given test might not be able to look at all mutations or every gene that causes a disorder, leaving a person who tests negative with doubt as to whether they are truly mutation-free. Some genetic tests, particularly those for complex disorders, are for susceptibility genes. As the name implies, these are genes that make a person susceptible to developing a disorder, but do not guarantee it. An example of this is breast cancer. When deciding whether or not to test for such a disorder, it is important to ask how it would feel to test positive for a susceptibility gene for a serious genetic disorder that may never develop.

The third consideration is risk of personal harm. Testing positive for a disorder may put a person at risk of economic or social harm. Although rare, there have been instances where individuals have been denied insurance, employment, or both based on the results of genetic testing. Also, a person may be at risk of experiencing psychological or emotional problems after undergoing genetic testing. There have been instances, particularly with Huntington's disease testing, where individuals have committed suicide following a positive test result. All of these factors must be presented to, discussed with, and weighed by the individual considering testing, in the context of genetic counseling and prior to making a decision about testing.

Presymptomatic Testing of Children

Presymptomatic testing of children has somewhat different considerations. It is typically considered only when the onset of the disorder occurs in childhood, or when knowing the genetic status will significantly benefit the child, for example by enabling him to receive early preventive treatment. For example, children at risk for inheriting the gene that causes retinoblastoma (cancer of the retina) may be tested because the disease usually presents before age five. With early treatment, the long-term outcome is favorable. Knowing whether the child has inherited the gene will allow physicians to know whether to aggressively screen the child for signs of cancer development.

Many genetic professional organizations have developed position statements regarding genetic testing of children that discourage testing for disorders that do not pose a risk in childhood and for which early identification poses no benefit to the child. This includes adult-onset disorders, such as Huntington's disease, but also pertains to carrier testing of females for X-linked recessive disorders, such as muscular dystrophy. In most X-linked (sometimes referred to as sex-linked) recessive disorders, females who inherit a mutation on one of their two X chromosomes are usually unaffected carriers because the second X chromosome is able to compensate for the loss. However, because males have only one X chromosome (the other sex chromosome is a Y), they will be affected if they inherit a mutation. In genetic medicine, personal autonomy is a priority. Individuals have the right to make their own decision regarding genetic testing. If a child is tested for an adult-onset disorder or to determine carrier status, their right to make their own decision as an adult has essentially been taken away.

Bibliography

Holtzman, Neil A., et al. "Predictive Genetic Testing: From Basic Research to Clinical Practice." Science 24, no. 278 (1997): 602-605.

Martindale, Diane. "Pink Slip in Your Genes." Scientific American 284 (2001): 19-20.

Ostrer, Harry, Richard H. Scheuermann, and Louis J. Picker. "Benefits and Dangers of Genetic Tests." Nature 392 (1998): 14.

Ponder, Bruce. "Genetic Testing for Cancer Risk." Science 278 (1997): 1050-1054.

Rennie, John. "Grading the Gene Tests." Scientific American 270 (1994): 88-96.

Internet Resources

"Secretary's Advisory Committee for Genetic Testing." http://www4.od.nih.gov/oba/sacgt.htm.

"Understanding Gene Testing." U.S. Department of Health and Human Services. http://rex.nci.nih.gov/PATIENTS/INFO_TEACHER/bookshelf/NIH_gene-testing/gene00.html.

—Susan E. Estabrooks

Any clinical or research assay that evaluates the genes, DNA sequence, or mutations in a specimen. This may include analysis of chromosomes, cells, enzymes, or molecular testing.

A process in which a person's or an embryo's DNA is isolated and tested for the presence of specific genes or defects that could indicate the future onset of some disease.

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)