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,2,**
* Center for Gastrointestinal Biology and Disease and Lineberger Comprehensive Cancer Center, School of Medicine, NC Center for Genomics and Public Health, and ** Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC 27599
2 To whom correspondence should be addressed. E-mail: tokeku{at}med.unc.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • genetic testing • DNA • genetic counseling • health professionals
The sequencing of the human genome has revolutionized our understanding of genetics and increased awareness of genetic susceptibility. Researchers are finding new genes for different disease conditions such as cancer, diabetes, and hypertension. The connection between genes and disease has become increasingly clear because it is now known that many diseases such as asthma, obesity, cancer, diabetes, hypertension, and heart disease have an underlying genetic basis (1). The advances in genetics have not only improved our understanding of the role of genetics in human diseases but have created more opportunities for genetic susceptibility research. Some of the research findings have been translated into clinical practice. Gene testing has become more important as clinically applicable tests become readily available. With increased public awareness about genes and diseases, there is an increased demand for more information about genetic diseases, genetic predisposition, and genetic susceptibility testing. For example, the improvement in our knowledge of the genes responsible for inherited colorectal cancer syndromes—familial adenomatous polyposis and hereditary nonpolyposis colon cancer—has resulted in better risk assessment and management of patients through genetic testing (2). The use of genetic testing may lead to improved surveillance strategies in people at risk.
Advances in genetics and genetic testing place greater burdens of responsibility on medical professionals and patients to fully understand the impact of genetic testing when it is used for diagnosis or for predicting future risk of disease. Genetic testing has far-reaching implications for the individual and family members. Health professionals should know the indications for gene testing and types of genetic tests to accurately interpret test results. The goal of this paper is to review the test characteristics and address genetic testing issues that health professionals should know.
What is genetic testing?
Genetic testing involves the analysis of DNA, RNA, chromosomes, proteins, and metabolites to detect abnormalities that may predict actual or future disease (3). The most common types of genetic tests use DNA or chromosomes isolated from blood. Genetic testing may also be conducted using amniotic fluid, cerebrospinal fluid, stool cells, and tumor cells. Genetic alterations are assessed by direct detection of abnormalities in genes or chromosomes using DNA-based tests or cytogenetic tests and other methods. Polymerase chain reaction (PCR)3, a process that involves the amplification of short segments of the genome, has revolutionized the field of molecular biology and genetics. Direct detection of alterations in genes involves extraction of genomic DNA from blood or tissue followed by amplification of the individual segments of the gene by PCR. The amplified fragment may be used in different ways to detect abnormalities. For example, direct sequencing of the PCR product is used in breast cancer susceptibility testing to detect mutations in BRCA 1 and BRCA 2. Cytogenetic tests use fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities such as duplications, deletions, rearrangements, and translocations (4). The FISH technique uses fluorophore-labeled short DNA sequences (DNA probes) unique to single genes or chromosomes to detect abnormalities. Wherever it finds a match, the labeled probe binds to complementary sequences on the patient's chromosome or DNA. The reaction is visualized by fluorescence microscopy and image analysis. For example, FISH is used to detect an extra copy of chromosome 21 in Down syndrome. Other tests use RNA, protein, or metabolites to test for genetic abnormalities. Examples of the different types of molecular genetic tests are listed in Table 1. Assays that detect mutations in genes responsible for some inherited disorders are currently available for routine clinical use. Up-to-date information about currently available genetic tests and laboratories that offer research and clinical testing for various genetic disorders are listed on the GeneTests internet site (5). It is important that health professionals be familiar with the different test methods so that they are able to interpret test results accurately.
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Genetic tests are used for many purposes, especially in the diagnosis of rare conditions in patients showing signs and symptoms of disease. Examples include Huntington's disease, medullary thyroid cancer, and colorectal cancer syndromes—familial adenomatous polyposis and hereditary nonpolyposis colon cancer (Table 2). Identification of mutations in the RET oncogene in a patient with thyroid cancer confirms the diagnosis of multiple endocrine neoplasia (MEN2) (6). Genetic testing has expanded to include tests that predict the probability of future risk of disease, detect the presence of a carrier state in unaffected individuals, and predict response to therapy in pharmacogenetics (7). Genetic tests are also used in making reproductive decisions. For example, a cystic fibrosis gene carrier may elect not to have an affected child by avoiding pregnancy or may chose to terminate the pregnancy if the fetus is affected. Routine testing is offered to pregnant women over the age of 35 to detect Down syndrome and other chromosomal abnormalities. One of the reasons often cited by parents for seeking genetic testing, either for reproductive or predictive risk assessment, is concern for offspring (8,9).
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If used appropriately, genetic tests can greatly improve the accuracy of disease risk assessment and identification of individuals in a family who may benefit from surveillance, surgical interventions, medical prophylaxis strategies, or potential family planning. The search is underway to assess the role of common genetic variants or single-nucleotide polymorphisms in genetic susceptibility to sporadic cancers and other complex multifactorial diseases. Polymorphisms may alter the function of the encoded gene product and are called common polymorphisms if they exist in at least 1% of the population. Polymorphisms in genes for DNA repair, metabolism, oxidative stress, and other functions are under study by researchers to determine their role in genetic susceptibility to cancer, heart disease, and diabetes. Single-nucleotide polymorphisms are detected by PCR analysis of DNA.
Who should be tested?
The criteria for deciding who should be tested will vary depending on the disease. However, obtaining a detailed family history that contains information about health, diseases, and cause of death for a minimum of three generations is recommended (13). This will allow identification of individuals who are at high risk and who might benefit from genetic testing, prophylactic measures, and surveillance. For example, current recommendations for the use of genetic testing in cancer families are that genetic testing should be offered to individuals with a strong family history of cancer or an early age of disease onset, if the test result can be adequately interpreted and if the test result will influence the medical management of the patient or family member (14). Inquiries by patients about genetic testing and genetic counseling may influence a physician's use (ordering a test or referring a patient elsewhere for testing or testing assessment) of cancer susceptibility tests (15).
Genetic testing issues for health professionals
Advances in molecular biology and genetics have increased the awareness of genetic testing, and this places unique demands on health professionals. Several important issues should be considered before genetic testing is recommended to patients. Genetic counseling is an essential component of the genetic testing process and should be offered to patients before and after genetic testing. Genetic counseling ensures that adequate family histories are obtained and that appropriate risk assessment and test selection are performed. In addition, genetic counseling helps patients deal with psychosocial issues that may arise as a result of the genetic testing. A study of the commercial APC gene testing process for patients and health care providers reported that informed consent was not obtained in 
80% of cases, patients received inadequate genetic counseling, and 31.6% of the providers misinterpreted the test results (16). This study and others illustrate the potential for misinterpretation of test results and miscommunication with patients as well as a need for better education of health professionals about various aspects of the genetic testing process (17). The genetic testing process involves knowledge about informed consent (18) and confidentiality (19), indications for genetic testing, types of tests, obtaining detailed family history including age of disease onset in family members, interpretation of test results, available treatment and prophylactic measures, referral resources for genetic testing and counseling, pre- and posttest genetic counseling, psychosocial effect of testing (such as genetic discrimination), insurance, loss of privacy, anxiety, and depression. To fully use the advances in genetics and genetic testing adequately in clinical practice, physicians and health professionals will need to keep up to date by using available educational resources such as published textbooks, workshops and courses, practice guidelines in genetics (available from different medical associations), information from the Centers for Disease Control and Prevention, and online resources on the internet (20,21). The GeneTests internet site is an invaluable resource that provides up-to-date and peer-reviewed information on the diagnosis, management, and counseling of genetic disorders as well as an international directory of laboratories conducting genetic tests (22).
Psychosocial consequences of genetic testing
Genetic testing has potential benefits and limitations for patients. Individuals with negative test results may experience relief but may also have feelings of survivor guilt and disbelief about the test result, and the negative results may have a negative effect on family relationships (23). Gene carriers may benefit from being able to reduce their disease risk by using available preventive measures as well as presymptomatic genetic diagnosis. Individuals with positive test results not only have to deal with the fact that they are at increased risk but, in addition, may experience anxiety and fears about the onset of disease and fear of passing the genetic mutations to their children (10), loss of privacy, and genetic discrimination by insurance companies and employers (8,9,24). The decision to receive genetic testing is not simple because individuals have to weigh the pros and cons of the testing and the possible impact of the test result on their lives. Medical decisions after a positive test result are difficult to make; therefore, health professionals need to have a proper understanding of people's perception of the potential benefits and harm of genetic testing so that appropriate support can be provided (25). Another issue that patients worry about is the cost of genetic testing; some patients may elect to pay the cost of testing out of pocket to avoid insurance discrimination.
Advances in genetics are likely to uncover new genes involved in complex diseases such as diabetes, hypertension, cancer, Alzheimer's disease, and others. This may increase the demand for genetic testing to predict individual predisposition to future illness in individuals with low-to-average risk and provide opportunities for preventive measures and early intervention. The advances in genetics and the constant changes in gene testing technologies present special challenges to health professionals. There is a need for better education of health professionals about the genetic testing process to improve patient care.
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FOOTNOTES |
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3 Abbreviations used: FISH, fluorescence in-situ hybridization; PCR, polymerase chain reaction.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Glazier, A. M., Nadeau, J. H. & Aitman, T. J. (2002) Finding genes that underlie complex traits. Science 298: 2345–2349.
2. Grady, W. M. (2003) Genetic testing for high risk colon cancer patients. Gastroenterology 124: 1574–1594.[Medline]
3. Holtzman, N. A. & Watson, M. S. (1999) Promoting safe and effective genetic tests in the United States: work of the task force on genetic testing. Clin. Chem. 45: 732–738.
4. Pergament, E. (2000) New molecular techniques for chromosome analysis. Ballieres Best Pract. Res. Clin. Obstet. Gynaecol. 14: 677–690.
5. Children's Health System and University of Washington. Seattle. Gene tests. Available at http://www.genetests.org (accessed July 20, 2003).
6. Weisner, G. L. & Snow-Bailey, K. Multiple endocrine neoplasia type 2 [MEN 2A (sipple syndrome), MEN 2B (mucosal neuroma syndrome), familial medullary thyroid carcinoma (FMTC)]. Available at http://www.geneclinics.org/profiles/men2/details.html (accessed July 5, 2003).
7. Burke, W. (2002) Genetic testing. N. Engl. J. Med. 347: 1867–1875.
8. Weitzel, J. N. (1999) Genetic cancer risk assessment. Cancer 86 (Suppl): 2483–2492.[Medline]
9. Hadley, D. W., Jenkins, J., Diamond, E., Nakahara, K., Grogan, L., Liewehr, D. J., Steinberg, S. M. & Kirsch, I. (2003) Genetic counseling and testing in families with hereditary nonpolyposis colorectal cancer. Arch. Intern. Med. 163: 573–582.
10. Hahn, M., Saeger, H. D. & Schackert, H. D. (1999) Hereditary colorectal cancer: clinical consequences of predictive molecular testing. Int. J. Colorectal Dis. 14: 184–193.[Medline]
11. Higashi, M. K., Veenstra, D. L., Kondo, L. M., Wittkowsky, A. K., Srinouanprachanh, S. L., Farin, F. M. & Rettie, A. E. (2002) Association of between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. J. Am. Med. Assoc. 287: 1690–1691.
12. Aithal, G. P., Day, C. P., Kesteven, P. J. & Daly, A. K. (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 variant. Lancet 353: 717–719.[Medline]
13. Ensenauer, R. E., Reinke, S. S., Ackerman, M. J., Tester, D. J., Whiteman, D. A. & Tefferi, A. (2003) Primer on medical genomics. Part VIII: Essentials of medical genetics for the practicing physician. Mayo Clin. Proc. 78: 846–857.[Medline]
14. American Society of Clinical Oncology. (1996) Statement of the American Society of Clinical Oncology, genetic testing for cancer susceptibility, adopted on February 20, 1996. J. Clin. Oncol. 14: 1730–1740.
15. Wideroff, L., Freedman, A. N., Olson, L., Klabunde, C. N., Davis, W., Srinath, K. P., Croyle, R. T. & Ballard-Barbash, R. (2003) Physician's use of genetic testing for cancer susceptibility: results of a national survey. Cancer Epidemiol. Biomarkers Prev. 12: 295–303.
16. Giardiello, F. M., Brensinger, J. D., Petersen, G. M., Luce, M. C., Hylind, L. M., Bacon, J. A., Booker, S. V., Parker, R. D. & Hamilton, S. R. (1997) The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N. Engl. J. Med. 336: 823–827.
17. Friedman, L. C., Plon, S. E., Cooper, H. P. & Weinberg, A. D. (1997) Cancer genetics survey primary care physicians and attitudes. J. Cancer Educ. 12: 199–203.[Medline]
18. Goel, V. (2001) Appraising organized screening programmes for testing for genetic susceptibility to cancer. BMJ 322: 1174–1178.
19. Holtzman, N. A. (1999) Promoting safe and effective genetic tests in the United States: work of the task force on genetic testing. Clin. Chem. 45: 732–738.
20. Snow, K. (2001) The growing impact of genetics on health care: do we have appropriate educational resources? Mayo Clin. Proc. 76: 769–771.[Medline]
21. Pagon, R. A., Pinsky, L. & Beahler, C. C. (2001) Online medical genetics resources: a US perspective. BMJ 322: 1035–1037.
22. Tarczy-Hornoch, P., Shannon, P., Baskin, P., Espeseth, M. & Pagon, R. A. (2000) GeneClinics: a hybrid text/data electronic publishing model using XML applied to clinical genetic testing. J. Am. Med. Inform. Assoc. 7: 267–276.
23. Hopwood, P. (1997) Psychological issues in cancer genetics: current research and future priorities. Patient Educ. Couns. 32: 19–31.[Medline]
24. Bleiker, E. M. A., Aaronson, N. K., Menko, F. H., Hahn, D. E., van Asperen, C. J., Rutgers, E. J., ten Kate, L. P. & Leschot, N. J. (1997) Genetic counseling for hereditary cancer: a pilot study on experiences for patients and family members. Patient Educ. Couns. 32: 107–116.[Medline]
25. Salkovskis, P. M., Dennis, R. & Wroe, A. L. (1999) An experimental study of influences on the perceived likelihood of seeking genetic testing. J. Psychosom. Res. 47: 439–447.[Medline]
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