Genetic Testing for Disease

Summarized by Robert W. Griffith, MD
May 8, 2006

Introduction

Genetic testing is progressing at a rate that's hard for us to keep up with. One of the latest advances is the application of testing to reach a diagnosis sooner than was previously possible, thus allowing earlier preventive or curative treatment. This is only one of the uses of genetic testing. The others include:

• Predicting disease
• Carrier testing
• Prenatal, pre-implantation, and neonatal testing

A good example of diagnostic testing is a report just published in the journal Cancer Research. It describes a test on sputum that could be used to identify people at high risk for lung cancer.

Sputum test for lung cancer

Lung cancer has a high mortality rate, with an average survival time of 13 months after diagnosis. However, early diagnosis, before tumors are advanced, can allow successful surgical removal; in such cases, a 5-year survival rate of 60% is achievable.

Scientists working in Albuquerque, New Mexico, base their approach on the fact that lung cells found in sputum show molecular changes (methylation of gene promoters) before lung cancer can be diagnosed. They tested the sputum of 98 people at high risk of developing lung cancer (i.e. heavy smokers with impaired lung function) for promoter methylation of 14 genes, and compared the results with those from 92 controls, who were matched by gender, age, and month of enrollment.

Tests were run annually, but only those provided by the cancer cases before diagnosis were analyzed, along with the corresponding samples from their matched control. The frequency of gene promoter methylation was determined for each of the 14 genes in both groups.

The genes from the cancer cases were, on average, 6½ times more likely to show promoter methylation than those from the matched controls. Looked at another way, the test correctly identified the 65% of those assigned to the lung cancer group who went on to develop cancer within the next 18 months. Unfortunately, 35% of the controls were also labeled positive by this test, although they didn't develop cancer in the same period.

Clearly, more work needs to be done before this test is ready for wide use to screen for detecting very early lung cancer. However, further analysis of subjects from cases and controls will allow the list of genes to be refined, so that the most predictable genes are included in the test. In this way, 'false positives' and 'false negatives' should disappear.

Other examples of genetic testing in diagnosis

In someone with symptoms of possible disease, genetic testing may be used to confirm or rule out a known or suspected disorder, such as Duchenne muscular dystrophy. DNA testing may provide diagnostic information at a lower cost and with less risk than other procedures. And it may sometimes have psychosocial implications for other family members. For example, in the case of fragile X syndrome, having a diagnosis may empower families by providing an explanation for a family member's physical, mental, or behavioral troubles.

Using genetic testing may not always be the best way to establish a clinical diagnosis. For instance, a mother may ask for DNA testing for cystic fibrosis. The doctor will tell her that a genetic test is available, but that sweat chloride testing is much more accurate and is the best way to tell if her child has the disorder. You can see that, for the most part, genetic testing can be used to help establish a diagnosis for relatively rare conditions that occur in the early years. There is less application for use in detecting common disorders in older folk, though it can be useful in prediction (see below).

Genetic tests for prediction purposes

Predictive testing identifies people who are at risk of getting a disease before any symptoms appear. This might be a test that screens for some inherited predispositions to certain forms of cancer, such as colon and breast cancer. Being predisposed does not mean that the individual will get the disease, just that the person has a certain risk of developing the disease.

An example of current interest is genetic testing for Alzheimer's disease. Familial Alzheimer's disease is a rare form, occurring in less than 10% of all Alzheimer's patients. It's early-onset, meaning it develops before age 65, and is caused by gene mutations on chromosomes 1, 14, and 21. If just one of these mutated genes is inherited from a parent, the person will usually develop early-onset Alzheimer's. The much commoner late-onset Alzheimer's has no known cause and shows no obvious inheritance pattern. However, researchers have identified an increased risk of developing late-onset Alzheimer's related to changes in the apolipoprotein E gene found on chromosome 19; one form of the apolipoprotein E gene is therefore called a risk factor for late-onset Alzheimer's disease.

There's no doubt that most people do not want to know if they carry such a gene, as Alzheimer's is a progressive condition without satisfactory treatment. The whole question of genetic testing in such circumstances is a matter of personal choice, influenced on one side by the increasing availability of tests, and on the other by the growth of the 'right not to know' movement (see link below).

Testing for carrier status

Genetic testing can tell someone if they are a carrier of an inherited disorder that they might pass on to their children. A person who has only one abnormal copy of a gene for a recessive condition is known as a carrier. Carriers don't get the disease, but they may pass on the defective gene to their children. Cystic fibrosis and Tay-Sachs disease are examples of such disorders.

Prenatal testing

Prenatal testing is used to examine an unborn child whose parents are at risk for having children with a chromosomal abnormality or an inherited genetic condition. It's often used to look for disorders such as Down syndrome, spina bifida, cystic fibrosis, and Tay-Sachs disease. Two procedures are commonly used: (1) Amniocentesis, that involves analyzing a sample of amniotic fluid from the womb, and (2) CVS (chorionic villus sampling), which involves taking a tiny tissue sample from outside the sac where the fetus develops.

Newborn screening

Newborn screening, at present the most widespread type of genetic testing, examines infant blood samples for abnormal or missing gene products. For instance, babies are commonly screened for phenylketonuria (PKU), an enzyme deficiency that can lead to severe mental retardation if untreated.

Who should consider genetic resting?

Who needs genetic testing? Persons in high-risk families living 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 may also eliminate the need for frequent checkups and exams such as an annual colonoscopy, which may be routine for high-risk families.

A positive test can also produce benefits. It can relieve uncertainty, and can allow a person to make informed decisions about his or her future. A positive predictive test creates an excellent opportunity for counseling and interventions to lower the likelihood of the predicted disease occurring.

A word of warning

Diagnostic laboratories now offer as many as 1000 different gene tests (see NIH link 'Gene tests' below). While improved prediction testing may provide better opportunities for individual prevention regimes, one must realize that medical insurance companies already have an almost intrusive interest in the likely future heath of their clients, and genetic testing may provide a tempting tool. Again, the 'right not to know' should be maintained . . .

Source

• Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. SA. Belinsky, KC. Liechty, FD. gentry,  et al., Cancer Res, 2006, vol. 66, pp. 3338--3344

Related Links
Genetic testing for Alzheimer's - the right not to know
NIH,NCI: Understanding gene testing
NIH: Gene tests

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