GENETIC TESTING

A NEW ERA OF MEDICAL CARE

INTRODUCTION Genetic tests use a variety of laboratory techniques to determine if a person has a genetic condition or disease or is likely to get the disease. Individuals may wish to be tested if: 1. There is a family history of one specific disease. 2. They show symptoms of a genetic disorder, 3. They are concerned about passing on a genetic problem to their children. Genetic tests include techniques to examine genes or markers near the genes. Direct testing for diseases such as cystic fibrosis and sickle cell anemia come from an analysis of an individual's specific genes. A technique called linkage analysis, or indirect testing, is used when the gene cannot be directly identified but can be located within a specific region of a chromosome. This testing requires additional DNA from an affected family member for comparison. Because each person's DNA is unique (except for identical twins), genetic tests also can be used for individual identification ("DNA fingerprinting"). Genetic testing is a complex process, and the results depend both on reliable laboratory procedures and accurate interpretation of results. Tests also vary in sensitivity , that is, their ability to detect mutations or to detect all patients who have or will get the disease. Interpretation of test results is often complex even for trained physicians and other health care specialists. When interpreting the results of any genetic test, one must take into account the probability of false positive or false negative test results. Special training is required to be able to analyze and convey information about genetic testing to affected individuals and their families.

TYPES OF GENETIC TESTING Carrier Identification includes genetic tests used by couples whose families have a history of recessive genetic disorders and who are considering having children. Three common tests include those for cystic fibrosis, Tay-Sachs disease, and sickle-cell trait. Prenatal Diagnosis is genetic testing of a fetus. This may occur when there is a risk of bearing a child with genes associated with mental retardation or physical deterioration. Down Syndrome is one of the most common genetic diseases screened by this method. Newborn Screening is frequently done as a preventative health measure. Tests usually have clear benefit to the newborn because treatment is available. Phenylketonuria and congenital hypothyroidism are conditions for which testing is conducted in all 50 states. Late-onset Disorders include adult diseases such as cancer and heart disease. These diseases are complex and have both genetic and environmental causes. Genetic tests may indicate a susceptibility or predisposition for these diseases. There are diseases caused by single genes, such as Huntington's disease, that also are seen later in life and can be tested at any time. Identification of genetic information belonging to a specific individual has received a great deal of press coverage lately. Profiles (aka "DNA fingerprints") are complied from the results of DNA testing for one or more genetic markers to identify unique characteristics of an individual. This information is currently used in legal cases involving paternity and in criminal investigations, and it can be used in time of major accidents, disasters, or wars to identify those who have died.

MEDICAL PROCEDURE

Genetic testing is often done as part of a genetic consultation and as of mid-2008 there were more than 1,200 clinically applicable genetic tests available.[7] Once a person decides to proceed with genetic testing, a medical geneticist, genetic counselor, primary care doctor, or specialist can order the test after obtaining informed consent. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a medical procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. Alternatively, a small amount of saline mouthwash may be swished in the mouth to collect the cells. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person's doctor or genetic counselor.

Routine newborn screening tests are done on a small blood sample obtained by pricking the baby's heel with a lancet. ETHICAL, LEGAL, AND SOCIAL ISSUES IN GENETIC TESTING Information from genetic testing can affect the lives of individuals and their families. In addition to personal and family issues, genetic disease or susceptibility may have implications for employment and insurance. Therefore, careful consideration in the handling of this information is very important. Critical issues include:

Privacy - the rights of individuals to maintain privacy. Some genetic tests are required or strongly encouraged for developing fetuses and newborn babies. If an infant is found to be a carrier or likely to develop or be affected by an inherited disease, these findings may affect the future employability or insurability of the individual. Informed consent - obtaining permission to do genetic testing. One must have knowledge of the risks, benefits, effectiveness, and alternatives to testing in order to understand the implications of genetic testing. Confidentiality - acknowledgment that genetic information is sensitive and access should to limited to those authorized to receive it. Future access to a person's genetic information also should be limited.

Gene testing is becoming a significant tool in standard medical care and perhaps most importantly in the search for the perfect drug to target a particular type of cancer. The detective work begins under the microscope. Here the scientist searches for clues in the genetic makeup of a patient's cancerous tumor. Inside that tumor could be as many as 13 major cancer genes containing 110 variations. Doctors hope this information will lead to a drug tailored to that particular type of cancer. "Every tumor has a genetic flaw which is driving that cancer, and if we can figure out for each individual tumor what that flaw is," Dr. Leif Ellisen said. Dr. Ellisen is a cancer specialist with Massachusetts General Hospital in Boston. "That will allow us to match the tumor to effective drugs," Doctors routinely try to match a drug to where the cancer is found in the body. For patients and doctors, that has often meant painful drugs or treatments that miss the mark. Massachusetts General is the first medical facility in the United States to conduct routine tumor testing. Lung cancer patients have been the first to undergo the screening. Dr. Alice Shaw of Massachusetts General says it is a major step toward customized medical treatment. "We have a much more sophisticated understanding of the genetic changes that occur in cancer. And hand in hand with that knowledge, we also have new and improved targeted drugs,"Dr.Shaw said.

Doctors found that genetic abnormalities in a breast cancer tumor, for example, appeared similar to abnormalities in tumors of the lung, and they thought these abnormalities might turn up in other tumors as well. That research led to tumor screening for all cancer patients who entered Massachusetts General. Linnea Duff has undergone genetic testing. "I was basically preparing for the end of my life," she said. Duff was diagnosed with terminal lung cancer. She had endured chemotherapy without success. Then her doctors found a genetic mutation that had only recently been identified. A drug targeted to that specific genetic abnormality was being tested. She took the drug, and her lung cancer disappeared. "It was really the most unbelievable, amazing thing. It was beyond my wildest dreams," she states. Some cancer specialists warn patients against placing too much hope in the screening. Cancerous tumors, they say, can sometimes be so full of genetic variations that it is hard to determine whether one test or treatment will mean a cure. But a few hospitals are following Massachusetts General's lead and are beginning tumor screening of their own cancer patients UNDERSTANDING INDIVIDUAL GENETIC VARIATION CAN HELP PREDICT CHEMOTHERAPY SIDE EFFECTS Currently, most patients receive the standard treatment; however, the side effects they suffer can be very different, ranging from severe to very minimal reactions. Making adjustments to treatment would have a major impact on both the physical and psychological well-being of patients, and on the financial burden to society posed by chemotherapy side effects, for example, hospitalisation. WHAT ARE THE LIMITATIONS OF GENE TESTING? First, current gene tests cannot provide a satisfactory answer for everyone who seems to be at risk for inherited breast or colon cancer. In some families, multiple cases may reflect shared environmental exposures rather than inherited susceptibility. Even when an inherited gene is to blame, it is not necessarily the test gene; the BRCA1 gene mutation, for example, is found in only about half of the families with hereditary breast cancer. Second, despite major advances in DNA technology, identifying mutations remains a great challenge. Many of the genes of greatest interest to researchers are enormous, containing many thousands of bases. Mutations can occur anywhere, and searching through long stretches of DNA is difficult.

In addition, a single gene can have numerous mutations, not all of them equally influential. The cystic fibrosis gene, for instance, can display any one of more than 300 different mutations, which cause varying degrees of disease; some seem to cause no symptoms at all. Thus, a positive test does not guarantee that disease is imminent, while a negative test - since it evaluates only the more common mutations - cannot completely rule it out. Furthermore, predictive tests deal in probabilities, not certainties. One person with a given gene, even one that is dominant like the hereditary breast cancer gene, may develop disease, while another person remains healthy, and no one yet knows why. A gene may respond to the commands of other genes or be switched on by an environmental factor such as sunlight. Perhaps the most important limitation of gene testing is that test information often is not matched by state-of-the-art diagnostics and therapies. Many diseases and many types of cancer still lack optimal screening procedures; it is often not possible to detect an early cancer even in an individual with a known predisposition. In inherited breast cancer, frequent screening with mammography offers the best chance of early detection, but falls short of prevention. Moreover, mammography is least effective in the glandular breasts of young women, the very ones at greatest risk from an inherited susceptibility. For the moment, the best assurance of prevention may lie in drastic and costly surgery to remove the breasts - but even a total mastectomy can leave some breast cells behind. As for the ovarian cancer that threatens high-risk families, available screening measures often cannot discover disease in time. Here, too, women in high-risk families often opt for prophylactic surgery to remove the ovaries. To date, however, neither type of prophylactic surgery has been proven to prevent completely the occurrence of cancer. Scientists are actively studying interventions aimed at the prevention of cancer. For example, ongoing clinical trials are evaluating the use of tamoxifen, an anticancer drug, as a breast cancer preventive. However, such approaches are still in the realm of research.

WHAT ARE THE RISKS OF GENE TESTING? The physical risks of the gene test itself - usually no more than giving a blood sample - are minimal. Any potential risks have more to do with the way the results of the test might change a person's life. Psychological impact. First, there are the emotions aroused by learning that one is - or is not likely to develop a serious disease. Many people in disease families have already seen close relatives fall victim to the disorder. The news that they do indeed carry the disease gene can elicit depression, even despair. Few studies to date have looked directly at the outcome of gene testing for cancer. One study found that, after 3 to 6 weeks, the women identified as gene carriers experienced persistent worries, depression, confusion, and sleep disturbance. Even half of the noncarriers reported that they continued to worry about their risk status.

What are the benefits of gene testing?

Persons in high-risk families live with troubling uncertainties about their own future as well as that of their children. A negative test - especially one that is strongly predictive - can create a tremendous sense of relief. A negative test, especially one that is strongly predictive, also may eliminate the need for frequent checkups and tests such as annualcolonoscopy (a procedure that allows a physician to view the upper reaches of the large intestine), which are routine for high-risk families concerned about cancer. A positive test can also produce benefits. It can relieve uncertainty, and it can allow a Conclusion on genetic testing person to make informed decisions about his or her future. Under the best of circumstances, a positive test creates an excellent opportunity for counseling and interventions to reduce risk. The prime example is colon cancer. When tumors are caught early, chances for survival are greatest, and screening potentially could prevent thousands of cancer deaths a year. A positive gene test sounds the alert to keep up regular screening practices (annual colonoscopies to check for precancerous polyps or the earliest signs of cancer) and to maintain healthful lifestyle measures such as a high-fiber, low-fat diet and regular exercise. Another option is surgery to remove the colon before cancer has a chance to develop. CONCLUSION Genetic testing is not a single technology. Rather, it refers to a broad range of methods for gauging the presence, absence or activity of genes in cells. At the relatively low tech end, researchers can count the chromosomes in a patient's cells or measure the amount of tell tale proteins in his or her blood. At the most sophisticated level, researchers assay a cell's DNA with molecular probes that can find a specific genetic sequence among the three billion base pairs that make up human DNA. (2) Genetic testing can cost less than $50 for a simple blood screening for sickle cell or cost in the $10,000 range for a complicated pre implantation genetic test for Tay Sachs disease. These are two extremes of genetic tests with varying costs.