Lost in translation
Washington
Scientists have long promised that the gene revolution would bring new tests to tell whether a person is particularly vulnerable to cancer, heart disease, Alzheimer’s disease and other ailments. By glimpsing the weaknesses coded in their genes, the reasoning has gone, people would be better equipped to alter their diet and behavior to avoid disease.
But the first major step toward these tests has gone awry in some cases, prompting questions about whether more federal regulation is needed and whether mass screening is even feasible for genetic predisposition to disease.
The problems have arisen in a test that tells people whether they carry DNA mutations for cystic fibrosis. In 2001, the American College of Obstetricians and Gynecologists recommended that doctors make the test available to every couple seeking care for a pregnancy or contemplating pregnancy so that they could determine the risk of producing a child with cystic fibrosis.
Because of the recommendation, cystic fibrosis screening has grown tenfold, to an estimated 200,000 to 400,000 tests annually. It is the first genetic test to be offered on a broad scale.
Now there is evidence that the test has sometimes done the opposite of what was intended, causing some people to add new risks to their pregnancies instead of helping them produce a healthy child.
In these cases, researchers say, confusion over how to interpret test results caused some people to believe mistakenly that their children were at risk for cystic fibrosis. As a result, some of them ordered amniocentesis or other fetal screening -- procedures that, while common, nonetheless present a small risk to the fetus.
In addition, the American College of Medical Genetics says it has received unconfirmed reports that some women aborted their pregnancies out of an erroneous belief that their children might have cystic fibrosis. Michael Watson, the group’s executive director, said these reports were “anecdotal.” Nonetheless, the group posted a “practice alert” at a March meeting saying that abortions in fact had occurred.
“This is heartbreaking. I’m deeply saddened,” said Kathy Hudson, director of the Genetics and Public Policy Center at Johns Hopkins University in Baltimore. “This is not what was intended when we started this screening. You should get accurate information from the test, not information that is worrisome and anxiety-producing but doesn’t have a whole lot to do with cystic fibrosis.”
The test looks for mutations in a gene related to cystic fibrosis, the most common fatal genetic disease in the United States, affecting about 30,000 Americans. If both parents carry a mutation, each child has one chance in four of having cystic fibrosis.
In those cases, the prospective parents can opt to test their fetus for the disease. The information can help parents prepare to care for a sick child or, in some cases, lead them to end the pregnancy.
However, the genetics of cystic fibrosis are complex. The test looks for the 25 mutations of the cystic fibrosis gene. But other elements in the DNA can amplify the effects of some mutations, boosting the severity of the disease.
The mutation R117H, for example, can cause a mild form of cystic fibrosis, but only when it appears in tandem with one of these other DNA elements, known as 5T.
For laboratories, the easiest course would be to test for 5T at the same time they test for R117H and the other cystic fibrosis mutations. But the American College of Medical Genetics recommends against this. It says laboratories should first determine whether a patient has the R117H mutation, and then test for 5T in a second and separate test.
The reason is that 5T is very common -- appearing in 5% or more of the population -- and by itself causes no problems. Testing for it on a large scale would turn up thousands of people who had 5T but no cystic fibrosis mutation, “and you’d have them all worried about something that does not cause cystic fibrosis,” said Dr. Wayne Grody, a UCLA genetics professor. By screening for R117H carriers first, laboratories would look for 5T only among patients who have a reason to worry about it.
However, one large laboratory, New Jersey-based Quest Diagnostics Inc., has been offering a test that includes 5T alongside the cystic fibrosis mutations.
This has led to some Quest clients being told that they had the 5T variation alone, with no R117H mutation -- information that the American College of Medical Genetics wanted to shield from patients.
Quest determined that at least 40 of these patients went on to request an amniocentesis or another test, even though they ran almost no risk of passing cystic fibrosis mutations to their children. The company said some of those patients would have ordered an amniocentesis anyway because of the age of the mother, but that 12 had no reason other than the 5T result for ordering the fetal test.
Quest publicized its study, alerting doctors to the problem.
“This is an example of what we’re going to see a lot of as we pursue a molecular approach to medicine,” said Dr. Edward McCabe, a pediatrician at UCLA. “As a practitioner, I’m extremely concerned about that. But as someone who is engaged in moving knowledge forward, I understand that knowledge is always evolving.”
Quest said it was taking steps to make sure doctors knew they could order a cystic fibrosis test without a 5T result, an option they always had but may not have been aware of.
In a separate problem, scientists now question whether one of the mutations in the cystic fibrosis test is truly a good indicator of the disease.
The two other major laboratories handling cystic fibrosis tests -- Genzyme Genetics of Westborough, Mass., and LabCorp of Burlington, N.C. -- said they test for 5T only after a R117H mutation has been found, in accordance with the professional guidelines. An estimated 50 smaller labs also conduct screenings, and their practices have not been surveyed.
The mutation, known as I148T, was included because it appears in people with cystic fibrosis.
But now that the screening test is widely used, I148T is also appearing frequently among people who do not have cystic fibrosis. Researchers now believe I148T must be paired with a separate variation, which does not appear on the cystic fibrosis test, in order to produce the disease.
Researchers presume that I148T results have prompted doctors to tell people erroneously that they carry a cystic fibrosis mutation. “Yes, patients have been told that,” said Dr. Deborah Driscoll, who practices reproductive genetics at the University of Pennsylvania. “But this is the kind of information that we learn only as we continue to do the testing. These panels are subject to change as we learn new information.”
As DNA testing for more diseases becomes available, doctors and patients will have to navigate other complexities.
Women with certain mutations in the BRCA 1 and BRCA 2 genes, for example, are thought to face a significantly increased risk of developing breast cancer. But experts say most women should avoid the testing.
That is because BRCA mutations account for no more than 10% of breast cancer cases, with environmental causes and unknown factors accounting for the rest. Experts say mass testing would cause many women to think their risk was low for breast cancer, when in fact their risk may be low only for the forms of the disease caused by BRCA mutations.
They say the genetic test is best suited for women whose relatives have been diagnosed with pre-menopausal breast cancer or ovarian cancer at any age, an indication that they carry a risk for inherited forms of breast cancer.
“Much as we’d like this to be straightforward, human beings are not straightforward,” said Dr. Garry Cutting, a cystic fibrosis specialist at Johns Hopkins University. “Genetics is full of nuance. Things aren’t black and white.”
Others said patients may not benefit from learning all the information that science can reveal about their genes -- especially during pregnancy, when people are particularly sensitive to signs of health problems. “Where do we draw the line and acknowledge that some information is so ambiguous that it’s not worth knowing?” said Dr. Wylie Burke, chair of medical history and ethics at the University of Washington in Seattle.
Hudson, of Johns Hopkins, said the confusion over cystic fibrosis screening showed the need for more federal regulation of genetic testing. Unlike drugs and medical devices, most genetic tests can be marketed without Food and Drug Administration approval. “It is startling that there is more regulation for the coloring in M&Ms; than there is for genetic tests, which can provide the information on which profound health decisions are made,” Hudson said.
The federal government could demand pilot studies of genetic tests before they are widely used. Once a test is on the market, regulators could force manufacturers and laboratories to report data that could lead to improvements in the tests, as Quest did voluntarily.
McCabe said an advisory panel to the Health and Human Services Department urged several years ago that the government review and approve new genetic tests before they were marketed. But the panel, which McCabe led, was also concerned that the requirement could create hurdles that would deprive patients of valuable new tests.
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Screening: step by step
* If you test negative for a cystic fibrosis mutation, you are not a carrier and the screening process ends.
* If you are found to have one mutant gene, you are a healthy carrier and should seek genetic counseling.
* Have your spouse or partner tested.
* If your partner tests negative, then the child will not have cystic fibrosis and the screening process ends.
* If the partner tests positive for a mutation, then the prospective mother can choose to undergo amniocentesis or another test that will determine if the fetus will develop the disease.
