Columbus Monthly / December 2010 / It's in the genes

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It's in the genes

Genetic tests can reveal your risk of getting a specific disease in the future. But do you really want to know?

 

The medical, moral and ethical issues behind genetic testing moved to the forefront of pop culture this fall when Meredith Grey, the protagonist in ABC’s medical drama “Grey’s Anatomy,” was working with a patient who had undergone genetic testing for Huntington’s disease. It got Grey thinking about whether her late mother’s early-onset Alzheimer’s disease was due to a gene mutation. The show ended with Grey asking a fellow physician to draw her blood for the genetic test.

In real life, researchers have pinpointed several mutations on four genes associated with Alzheimer’s. The mutations on three of those genes are associated with early-onset Alzheimer’s, but, according to the Alzheimer’s Association, fewer than 1 percent of all cases of Alzheimer’s are due to genetic factors.

If a person tests positive for one of those mutations, it is almost a guarantee that they will develop early-onset Alzheimer’s, according to the U.S. National Institutes of Health. But even if a patient such as Grey tests negative for the gene mutation, it’s no guarantee she won’t get Alzheimer’s at some point in her life.

The case demonstrates both the appeal of genetic tests and their limitations. While the results may be useful in making decisions about your health, scientists don’t yet know everything there is to know about the rapidly evolving field of genetic science.

Using the tests

Genetic testing—and all of the issues and questions surrounding it—made a huge leap earlier this decade when the Human Genome Project was completed in 2003. The project, initiated by the U.S. Department of Energy and the National Institutes of Health in 1990, mapped and sequenced the entire human genome. The increased availability of genetic tests was one of the most immediate effects of the project.

Genetic tests, frequently just a blood test, says Robert Pyatt, assistant director of the molecular genetics and cytogenetics laboratory at Nationwide Children’s Hospital, analyze human DNA, RNA, chromosomes and protein. The tests search for a mutation or substitution somewhere that would cause a disease.

The tests can be used to screen for or diagnose a genetic disease in a newborn, child or adult. The tests also can identify a person’s risk of getting a specific disease in the future and assess his or her risk of passing it on to children. The results of genetic tests may even be used to predict a person’s drug response in a field known as pharmacogenomics, an area that also resulted from the Human Genome Project.

The field of pharmacogenomics is promising, because it will help medical professionals better determine how a person’s body will respond to certain drugs based on his or her genetic makeup, says Amy Sturm, clinical and assistant professor at Ohio State University Medical Center and a genetic counselor.

Sturm’s main research interests are in cardiovascular health and the risk assessments and tools associated with that area. One of the research trials Sturm says she’s particularly excited about is a research partnership with the internationally recognized nonprofit Coriell Institute for Medical Research, based in Camden, New Jersey. The genetics study, called the Coriell Personalized Medicine Collaborative, also includes patients from four other centers across the country. It aims to provide more information on why drugs work differently from one person to the next and to pinpoint unknown variances in genes that give some individuals a higher risk for certain diseases.

Ohio State will be enrolling 1,800 patients in the study, Sturm says. Half will be people who have been diagnosed with heart failure, the other half with newly diagnosed high blood pressure. Ohio State will work with the patients’ primary-care physicians and cardiologists as well, so their doctors will receive better information on treating their patients as a result of the study, she says.

“We’ll be finding out why some people respond better to treatments or if a certain drug works better for them than others,” Sturm says, adding that Ohio State hoped to begin enrolling patients in the study by early November. “Individuals will remain on the study for at least five to 10 years.”

Sturm is one of several genetic counselors at Ohio State. While she works mainly on cardiovascular issues, an area of genetics research that is still fairly new, other counselors work on research having to do with cancer.

There are seven genetic counselors at Ohio State in the clinical cancer genetics program who work on cancer counseling only, explains Heather Hampel, a certified genetic counselor and a professor in the division of human genetics. The two most common genetic tests that the department runs are for hereditary breast and ovarian cancer and for Lynch Syndrome, says Hampel. A positive test for Lynch Syndrome means the person has an increased risk of developing colorectal or endometrial cancer. “Those four solid organ tumors are where we do the vast majority of our work,” she says.

OhioHealth also has a genetics program that primarily tests for breast cancer, but also colon, ovarian, uterine and thyroid cancers, says Nichole Morman, a certified genetic counselor with OhioHealth. Of the 300 or so patients who go through its department each year, “probably 80 percent or so are coming because of a concern about breast cancer,” Morman says.

Nationwide Children’s Hospital has a genetics program that works closely with the rest of the medical community as well as with scientists at Children’s who are researching genetic links to diseases that most often present themselves in childhood, Pyatt says. “There are diseases that we understand the genetics of very well, and there are those diseases that are more in the research phase.”

Difficult decisions

There still are questions surrounding genetic testing. A major one for patients: Do you really want to know you have a genetic predisposition for a particular disease if you can’t do much about it?

“That’s definitely going to be a medical decision,” Morman says. With certain diseases—Huntington’s disease or Alzheimer’s disease, for example—the knowledge that you have the gene mutation can give you time to prepare, she says. There’s also a mental aspect to it, she says; if Huntington’s disease runs in the family, family members might wonder about every little thing that happens, waiting for the ball to drop. “They might think, ‘OK, I lost my keys today. Does that mean I have Huntington’s disease, or did I just misplace my keys?’ ”

Ethical issues also factor into whether a person should have a genetic test, Morman says: “If I have children, is there anything I can do to prevent passing the gene along?”

Genetic counselors are adept at helping people who are struggling with the issue, Hampel says. “We kind of tailor the recommendations depending on what cancer they’re at risk for.” For instance, if the test for Lynch Syndrome is positive, she says, it provides a patient with important information that could help him prevent the development of the cancer. While normal low-risk patients are advised to get colonoscopies starting at age 50 and then every 10 years, a person deemed to have a higher risk of developing the cancer because of Lynch Syndrome would get his first colonoscopy at age 25, and then every one to two years.

“With colon cancer, the vast majority start with polyps,” Hampel says. “Here you can stop the cancer from occurring by removing that polyp.”

There are cancers, though, where very little can be done to help the patient, and that’s where genetic counseling can help people decide whether they even want the test.

A specific form of gastric cancer, for example, creeps around the wall of the stomach and then pushes through, Hampel says, adding that it’s difficult to pick up with screening tests. When that cancer develops—or if a person knows he is at risk for getting it—the treatment would be the surgical removal of the stomach, obviously a serious issue to decide, she says. A factor that comes into play at that point is whether the genetic test might help others in the family, she says.

“Sometimes there’s comfort in knowing there’s a gene factor,” Hampel says. “You want to be able to tell your family whether they’re at risk, or no, they’re not.”

Different people handle the news in different ways, she says, recalling one family whose genetic tests showed the breast cancer in their family was hereditary. Two sisters in the family tested positive for the gene mutation. One sister chose to reduce her risk by having a mastectomy, while the other opted for increased monitoring through more frequent exams and mammograms. The first patient said she never wanted to hear the words, “You have cancer.” Her sister said she could not fathom having her breasts removed if she didn’t have cancer. Each woman made a personal decision with the help of genetic counseling. “Both approaches are fine,” Hampel says, “because we know both work.”

On the research side of things, genetic testing can be used to determine whether a patient is a good candidate for a certain therapy, Pyatt says. Children’s Hospital has a Center for Gene Therapy that researches and uses gene therapies to prevent and treat a number of diseases, from neuromuscular and neurodegenerative diseases to neonatal hypertension, cancer and infectious diseases.

Children’s is able to do pre-implantation genetic testing to check for a gene mutation in an embryo before it’s implanted in the mother’s womb. The laboratory also does a lot of prenatal genetic testing. For example, if an expectant mother whose blood tests indicate a high probability that the baby she’s carrying will be born with Down syndrome, she may choose to undergo more genetic testing to see if that genetic mutation exists. If it does, the parents are armed with information that will help them makes personal choices and plan for the future.

“Everybody uses the information from testing a little bit differently,” Pyatt says. “Some people want to know and some people don’t. Some people suffer from a form of guilt knowing that they passed this on. Some people are happy to know the cause.”

Accuracy rates

Part of what is making such decisions possible is that genetic tests are very reliable, given the right set of circumstances, Hampel says. “The tests themselves involve sequencing of the genes, so they’re extremely accurate.”

The ever-changing and advancing technology of gene testing means only good news for accuracy, Pyatt adds. “The accuracy depends on the methodology,” he explains. “We do things to increase our accuracy. For example, we can repeat the sequencing over and over.”

The best outcomes occur when a family member with the disease is still alive, Hampel says. In that situation, scientists can run a genetic test on the affected person to find out if the illness is due to a genetic problem. If it is, then all other family members can be tested for that specific mutation. If they test positive, they know they’re in a higher-risk population.

If the person with the disease has already died, other family members still can get tested, but the results are in something of a gray area, Hampel says. A positive test for a specific mutation is a definite positive, whether the person with the disease is living or dead. But a negative test result for a person whose parent has already died is not a sure thing.

“You don’t know if the test result is negative because it’s a true negative and you didn’t inherit it, or if it’s a negative because the mom or dad didn’t have the gene mutation,” Hampel explains. “You can’t ever get them to a true negative.”

The tricky part of genetic testing comes with the knowledge that the tests search only for gene mutations scientists already know about, Hampel says, again pointing to the ambiguity in a negative test result. The negative result could mean it’s truly negative, or it could mean there is in fact a mutation, but it’s in a gene scientists don’t know about yet, she says.

With genetic testing in cardiovascular diseases, the same can be true, Sturm says. “When you have your testing done—for example, with hypertrophic cardiomyopathy—it’s a panel of genes that are responsible,” she says. “We know there are several we haven’t discovered.”

So if the test is positive, researchers know it’s a certainty—but in a few cases, questions still linger.

“The problem is, about 5 percent of the time with this cardiac testing, there is a variance of uncertain significance,” Sturm says. In those cases, it’s difficult to determine where the variance is significant—if it’s a brand new change they’ve never seen before in a gene, or if it’s the true mutation for which they were hunting. “That’s why it’s good to have genetic counseling before they have the genetic testing,” she says, “so they can understand it.”

Managing diseases

Even with the questions that sometimes arise, genetic testing has evolved to a point where results are reliable enough for doctors and patients to use them in making decisions about their health and in managing diseases or minimizing the risk of contracting certain diseases. Hampel and others see this most often in the treatment of breast cancer.

She recalls one patient who was an oncology nurse whose paternal grandmother had breast cancer. There’s a persistent myth that the hereditary factor for breast cancer can’t be passed down through the father, but that is false, Hampel says. In the nurse’s case, her father was a carrier of the breast/ovarian cancer gene, and, “She did in fact have breast/ovarian cancer.”

People whose families have the gene mutation for breast/ovarian cancer are in a high-risk population. “But the newest thing here is that [genetic testing] is starting to definitely affect the management of cancers,” Hampel says.

When faced with a diagnosis of breast cancer, many women must ultimately decide whether to have a lumpectomy to remove the cancerous tumor, or a bilateral mastectomy. The decision is a personal one that women make with medical counseling. If they have the information that their breast cancer is hereditary—a factor that puts them at a much higher risk of a recurrence—they might choose to have a mastectomy to lower their risk of recurrence.  

The field of pharmacogenomics comes into play here, too, Hampel says. Two separate clinical trials funded by the National Cancer Institute are currently underway at Ohio State. Each trial combines chemotherapy with an agent that targets the pathway for the gene mutation;
with the pathway blocked, the cancer cells die or weaken and become vulnerable to the chemotherapy agents.

With that information, “You might treat a patient differently, with a different chemotherapy agent,” Hampel says. “That’s the whole way we wanted it to go. It’s just taken a long time to get there.”

Insurance issues

There was a time when patients and doctors were fearful about the impact a positive genetic test would have on insurance rates or availability of insurance, Hampel says, adding that some doctors even kept shadow charts to protect a patient’s insurability. The risk of losing their insurance “would keep people from coming to see us,” she says.

Times have changed.

A federal law—the Genetic Information Nondiscrimination Act of 2008—and state laws prevent insurance companies from dropping a person’s insurance, denying coverage or raising individual rates due to a positive genetic test result.

Insurance companies also are beginning to concede that while a genetic test can be expensive, it might save them money in the long run. “I think what they’re beginning to realize is that it’s a lot cheaper to pay for these genetic tests and the increased cancer screenings than to pay for stage IV cancer treatment,” Hampel says.

The same holds true for the cardiac tests, Sturm says. “They are getting smart,” she says of insurance companies. “They’re saying, ‘Hey, I could pay a few thousand dollars for this test and maybe know I won’t have to pay for yearly echocardiograms.’ A lot are getting very good at treating it just like any other test.”

“Most carriers have criteria,” Morman says. “If the patient meets that criteria, then they’ll cover it.”

Neither the state nor the federal law covers long-term care, disability or life insurance. “We do tell people to get your life insurance established before you have a genetic test,” Sturm says.

Pyatt, however, says his experience with insurance coverage has been different. If he had to rate it, he says, he would say it’s “OK to not so hot” when it comes to insurance companies’ willingness to cover certain genetic tests. But part of the problem, he admits, is that the science behind it is growing.

“Human genetics is changing so much right now,” he says. “I think the insurance companies are having a hard time keeping up with that. There’s a lack of understanding, just because things are changing so fast.”

But it’s that new research that makes this such an exciting time in genetics, he says. “Our understanding of ourselves changes every day,” he says, and that’s good news for people who think they might be at risk for a certain disease. As information is uncovered, new tests are invented and new clinical trials are funded.

“If someone comes to see us, we always let them know if there’s a study they are eligible for,” Sturm says.

Sometimes, though, people just wonder. Maybe a parent and some aunts and uncles had different types of cancers, or several family members have died of heart disease. Doubts linger in people’s minds about whether those diseases were due to a genetic factor, Sturm says.

“If anyone has questions, I think the good thing is to ask your physician to make the referral to a genetic counselor,” Morman says. “We can see people who are low-risk.” OhioHealth also employs two nurses who will review a patient’s family history over the phone at no charge. Those nurses, she says, can ask questions and get more information from the patient to help them decide whether they should pursue testing.

Ohio State offers Family HealthLink (familyhealthlink.osumc.edu), an online assessment tool that people can use to plug in details about their family history and get information on whether their risk is high, moderate or average for developing cancer or coronary artery disease. If the tool determines you are at higher risk than most people in the general population, it recommends that you consult with a genetic counselor for a more complete assessment and to learn what you can and can’t do to lower your risk of developing a disease.  

 

Michele Lemmon is a freelance writer.