FIFTY-FIFTY. Susannah Gilbert was well aware of her odds, but in the cramped counseling room at UW – Madison’s Paul Carbone Comprehensive Cancer Center, she heard her genetic counselor go over them once more. It was a flip of a coin, a 50 percent chance that she had inherited her mother’s Lynch Syndrome, the genetic disorder that had caused her repeated battles with cancer. Although she was only 16 years old—active, healthy and hardly of the age to worry about cancer—Susannah knew that her own DNA was keeping a secret from her. And she was ready to know the answer.
With her parents by her side around the Formica-topped table, Susannah nodded in quiet understanding. The Gilberts had been through this before. A few months earlier, Susannah’s older sister, Emily, had been tested for the disorder, and the whole family rejoiced when they discovered she didn’t have it. But privately, Susannah worried. “It felt like one of us should end up with it,” she confessed later. “I felt like I had a higher chance of having it somehow because she didn’t.” Now, it was her turn to learn the truth—information that would set her down one of two paths. Down one lay rigorous annual cancer screenings and the likelihood of surgeries, radiation and chemotherapy. The other path held the deceptively simple promise of a normal life.
For nearly two hours, Amy Stettner, who counsels patients through genetic testing for the UW- Madison-affiliated Waisman Center, walked Susannah through the steps that she would take to find out which path her life might follow. First, Susannah would provide a sample of her blood, which would be packed in a small tube and shipped to a lab in Salt Lake City, Utah. There, lab technicians would perform PCR amplification on the sample to hone in on a key part of her DNA. They would look for the presence of a small error in her genetic code in a process akin to checking to see if a book has a particular typo on a particular page. Once their testing was done, they would check one of two boxes on a form, either “No Mutation Detected” or “Positive for Deleterious Mutation.”
Then, two weeks later, Susannah would return to the small counseling room to learn the results. Either way, the test would reveal a deeply intimate piece of information about her, a glimpse into the very makeup of her being. On that day, she would discover information that, once known, could never be unknown. For better or worse, she would learn what her body might have in store for her future.
Sarah Gilbert was 31 years old when she got her first cancer diagnosis. She had been sick for more than a year, and she was shocked to learn she had been suffering from colon cancer. But then, after surgery to remove the tumor, it was gone. Three years later, Sarah was given a clean bill of health. She and husband Peter, who had just finished a master’s degree in library science at UW – Madison, decided to celebrate by having a second child. “Susannah was sort of our victory baby,” says Sarah.
A few years later, Sarah started having unusual menstrual periods. By then, the family was living in Appleton, Wis., where Peter had taken a job in Lawrence University’s library system. Thinking she was experiencing early menopause, Sarah tried alternative medicine. But doctors discovered something else: her second and possibly third cancers. “They couldn’t exactly tell from the pathology whether I had stage three uterine cancer that had spread to my ovary, or stage two uterine cancer and stage one ovarian cancer cropping up at the same time,” says Sarah. To be safe, Sarah was treated for both. She had a complete hysterectomy, followed by radiation therapy for her uterine cancer and chemotherapy for her ovarian cancer.
By this point, Sarah and her family were convinced that this was more than a string of bad luck. Sarah’s sister, a doctor living in Indianapolis, had recently read about Lynch Syndrome, which seemed to explain Sarah’s litany of cancers. Caused by a mutation in a gene that helps ensure DNA gets coded correctly when cells grow and divide, Lynch Syndrome carries a significantly elevated risk of developing tumors, especially in the colon (see box, page 32). While most people have a 2 percent chance of developing colorectal cancer during their lifetime, for instance, people with Lynch Syndrome face an 80 percent likelihood. Their odds of a second colorectal cancer within 15 years are 50-50.
But before Sarah had a chance to be tested for Lynch Syndrome, she was again diagnosed with cancer. This time, surgeons removed most of her colon, followed by three months of chemotherapy that were made tortuous by blood clots and infections. All this before she turned 44.
It came as little surprise, then, that her DNA tested positive for Lynch Syndrome. “I was actually happy to find out something so concrete, and that it wasn’t my lifestyle, it wasn’t my fault somehow,” says Sarah. “I mean, this was just somehow in the cards I was dealt, so it was okay.”
Although Sarah’s parents and siblings were also tested for the defective gene, none proved to have the mutation. “Part of me wanted to have the Lynch Syndrome gene just to support her,” says Sarah’s brother Michael Holt, an emergency room physician at St. Mary’s Hospital in Madison. Holt had planned to have T-shirts made to show off the family’s faulty genetic code. Instead, Sarah discovered that she was the originator of a spontaneous mutation—a freak occurrence that took place inside one of the early embryonic cells that gave rise to her being.
Sarah’s daughters, however, faced a different situation. They knew they stood a 50 percent chance of inheriting the faulty gene from their mother, a gene that would trump the effects of the working gene they received from their father. They also had an option their mother never did: They could be tested for the mutation before any appearance of symptoms. They could get an early warning.
The ability to test one’s genes—practically unheard of even 20 years ago—has grown out of the dramatic advances in genetics research. Scientists, including many working in CALS and UW-Madison’s other life-sciences colleges, have made breakthrough discoveries that have opened up huge portions of the human genetic code to inspection. By identifying and sequencing the genes underlying a host of genetic conditions, this science is revolutionizing medicine. Already, genetic tests exist for some 900 disorders, including cystic fibrosis, Duchenne muscular dystrophy and Lou Gehrig’s disease, and many more are developed each year.
With such tests, doctors are gaining the ability to identify genetic conditions years before they ever make themselves apparent and treat patients according to their unique genetic makeup. But genetic testing has also created an entirely new kind of question, a personal, emotional dilemma that Emily and Susannah Gilbert have faced head-on: If you had a genetic disease that might not emerge for years, if ever, would you want to know?
On one level, the answer seems easy. With the completion of the human genome project, which sequenced the sum total of human DNA, genetics researchers have created a mountain of data about the genes that define nearly every facet of our being—not only whether we’re blue-eyed or brown, or will lose our hair as we age, but also whether we are predisposed to diseases like breast cancer or hemachromatosis, an iron storage disorder. Knowing our genetic vulnerabilities can undoubtedly improve—or even save—our lives. “We are all genetically flawed in some way, and knowing what those problems are really gives you a tremendous advantage, in terms of having personalized healthcare,” says Amy Stettner, the Gilberts’ genetic counselor. She cites an example of a 30-year-old woman who has a mutation making her more likely to develop breast cancer. “I think every doctor taking care of you needs to know that, including the radiologist that reads your mammogram. If it’s not clearly evident that you are a carrier, they are not going to look at your mammogram the same way.”
But as science sheds light on wider sections of our genetic code, the data we can amass about ourselves is piling up. Biotechnology companies are springing up to sell the ability to read your own DNA. In one case, customers simply mail a saliva sample to a laboratory and get online access to swaths of their genetic code, where they can surf for telltale signs of various genetic disorders.
“Not very far from now—two years, three years, five years—it’ll be economically feasible to take a small amount of blood and analyze your whole genome,” predicts Norman Fost, director of UW-Madison’s bioethics program. “And what that means, for one, is that patients will be just flooded with information, just complete sensory overload.”
The larger question is whether this information glut will ultimately benefit patients. Fost points out that the ability to test always runs ahead of the ability to treat. While medical therapies exist for genetic disorders such as PKU and cystic fibrosis, he says genetic testing will identify “more and more disorders for which there are no effective treatments.”
One such example is Huntington’s disease, the degenerative brain disease that killed singer Woody Guthrie. In such cases, “it’s not clear whether the benefit of prior knowledge outweighs the burden for many patients,” Fost says.
Fost worries, too, about tests that show modest predispositions to diseases. What should a man do if he finds out his risk of developing diabetes is 30 percent higher than average? Does he give up sugar? Start taking medication? And if so, at what age?
“A genetic test is good when the test is linked to something that’s useful for the patient,” says Fost. “Knowledge by itself is not good. Knowledge is good only if it leads to something else that makes your life better.”
In the case of Lynch Syndrome, early identification does have some clear benefits. Although there is no cure or treatment, a positive test can allow doctors to more aggressively monitor patients for signs of early cancer. Lynch Syndrome patients generally start undergoing annual colonoscopies at age 20, for instance, and women have more-extensive gynecological exams to monitor their uteruses and ovaries. Most are advised to have preventive hysterectomies in their late 30s.
But even life-saving knowledge can have fallout. The revelation of a severe genetic disorder can affect how people feel about themselves and their families, potentially altering dreams of pursuing certain careers or raising children. Many patients also worry about discrimination: Will identification of a genetic disorder affect their ability to work in certain fields or obtain health insurance? Despite the significant progress made in 2008 toward an anti-genetic discrimination bill, such worries seem valid. As Fost points out, genetic labels are “very sticky, particularly if they get in your medical record.”
These issues troubled Peter and Sarah Gilbert as their girls grew up. What if Emily and Susannah had Lynch Syndrome? Testing them at a young age might benefit their health, but what about their psyches? And what if they didn’t have it? Finding that out could relieve them of the stress of not knowing and save them the hassle of rigorous medical examinations. Ultimately, they decided it was up to the girls. When they were old enough, they could choose.
Both Emily and Susannah had been home-schooled, and purely by virtue of being at home day in and day out, they had come to understand what living with Lynch Syndrome would mean. Even though their mother had been cancer-free for seven years, they had watched her suffer through bouts of painful digestive blockage and dehydration due to her scar-tissue-riddled colon. Her surgeries had created a situation where, as Sarah jokes, “food doesn’t like to go through me.” Periodically, she requires additional surgery to clear her intestinal tract.
Initially, Emily Gilbert thought she didn’t want to know if this is what her future held. When she turned 21, she changed her mind and took the test. “After a while, I decided it would be better if I did because I tend to worry about things,” says Emily, who works part-time at Heritage Hill State Historical Park, a living-history museum located in Green Bay. “I realized I’d fret over (not knowing) a lot more than knowing for sure one way or the other.”
When Emily’s test results arrived in the spring of 2007, Stettner had to deliver the news over the phone. Sarah was in the hospital that day with digestion problems.
Susannah admits she felt ambivalent about her sister’s test result. “I felt like I should be really happy for her, but it was hard because that is when I said, ‘Okay, I definitely think I have it now,’” she says. She asked to be tested shortly thereafter, but both Sarah and Stettner agreed that it would be best for the sake of sibling harmony if Susannah waited a bit longer. “We both thought, ‘Let’s let Emily enjoy this for a little while,’” says Stettner. “If Susannah tests positive, all of the sudden all of the attention will be focused on Susannah, and the happiness from Emily’s result will be overshadowed.”
Six months later, Susannah again said she was ready. There was some hesitation about her age: Generally, minors aren’t given genetic tests out of concern that they don’t have the emotional maturity to cope with the results. But Stettner had worked with the Gilberts long enough to know that Susannah was special. She was a thoughtful young woman who explored her ideas through writing and photography. She understood the disease. She understood the odds. And most of all, she wasn’t fazed by what the test might mean.
“To a lot of kids my age, cancer is this big scary thing. (To them,) people get cancer and die,” Susannah says. “To me, it’s part of my life. It’s part of how I grew up. I just want to know so I can process (it), make plans and get on with my life.”
Two weeks passed, and Susannah returned to the counseling room in the cancer center. Stettner sat down at the table and exchanged brief pleasantries with Susannah and her parents. But this time, there was no long discussion about statistics. Stettner turned immediately to her results.
Susannah was positive.
Susannah’s face reddened, and water welled in her eyes. She stared at the table, afraid to look at her parents and lose what composure she was managing to hold on to. Stettner waited, letting the emotion roll over her. Susannah exhaled deeply, then looked up, ready to listen again.
There was more talk about Lynch Syndrome and how good it was to know early. Then the Gilberts drove home. In the car, Susannah slept, while Sarah stared ahead in silent reflection, moving through waves of successive emotion. She felt sadness and guilt, but also hope that Susannah’s cancers would be caught much sooner than her own had. And she realized that she was no longer alone.
Possessing a genetic mutation can be a lonely burden, especially for a rare condition like Lynch Syndrome, which affects only a fraction of 1 percent of the U.S. population. When Sarah had been diagnosed, she had set out to contact others with the disease, hoping to form a support group in her area. She soon realized that there weren’t any others to be found. She once wrote a poem expressing her envy of breast cancer survivors, with their immense support network and pink ribbons. There were no ribbons for Lynch Syndrome.
But Sarah has found comfort in her family, who have accepted her struggles with light-hearted grace. They helped Sarah find the humor in her condition, joking that she should have a zipper installed on her abdomen to give doctors easy access. Now she could provide that support for her daughter.
“It would be a happier thing if I was an island. But, on the other hand, what a bonding,” says Sarah. “And maybe I can help Susi just by being a survivor and being there for her—a little camaraderie.”
As they neared Appleton, Sarah called Emily, who had stayed home to cook one of Susannah’s favorite dinners, lasagna. Emily had been on tenterhooks all afternoon, and the news was deflating. “I felt sort of guilty that she had it, and I didn’t,” says Emily. That night, the family watched a movie. Nobody talked about the test. Two months later, the sisters still hadn’t talked about it directly.
Talking about it, in fact, turns out to be the worst part, Susannah says. At least for now. “One of the hardest things has been telling my friends, because teenagers don’t do this sort of thing well. They either blow it off or start looking at you like you’re terminally ill,” says Susannah. Adults aren’t much better. Susannah doesn’t like hearing about her “strength.” Nor does she like saccharine assurances about the phenomenal leaps and bounds medicine will make in upcoming years.
For now, Susannah’s day-to-day life is very much the same. During the day, she studies under the guidance of her mom. She babysits the neighbor kids for extra cash and spends it hanging out with friends. She is learning how to drive. The banality of it all “kind of bugs me in some ways,” she says. “There’s nothing I can do right now. I just know.”
But there are other signs that the tiny mistake in Susannah’s DNA has begun to creep into her consciousness, defining more than just her biological function. “I think it’s going to be one of those things that’s always just at the back of my mind whenever I’m making decisions,” she says. “The doctors have said that if I want to have kids, I need to have them young, like before I’m 30 preferably, because that’s when mom got her first cancer. It’s kind of weird to have to think about that now, and to (know that) if I want to get married I need to find somebody who I know can handle going through this with me. In some ways, I’m thinking farther ahead than I should have to.”
This fall, Susannah starts her junior year in high school. Although she’s determined to take life as it comes, she knows bigger challenges are ahead. Right now, she’s thinking about college. “The other day,” she says, “I said to myself, ‘I should find one near a nice hospital.’”