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Sequencing, Though Not Always a Slam Dunk, Gains Traction in Genomic Medicine

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Next-generation sequencing is steadily gaining acceptance in the healthcare community, but even ardent supporters of the technology cautioned at a recent conference that the approach should not be considered a silver bullet that can solve all previously intractable medical cases, but rather should be viewed as one tool among many that doctors can use to gather evidence to improve patient care.

Some of the first clinical sequencing cases attracted a great deal of attention because they were unqualified success stories. For example, in 2010, Nic Volker, a 6-year-old boy with an extreme form of inflammatory bowel disease, had his exome sequenced by doctors at the Medical College of Wisconsin and the Children’s Hospital of Wisconsin who found a mutation associated with an inherited immune disorder. After undergoing a cord-blood transplant, Nic is still doing well today. Another case involved the twin children of Life Technologies' chief information officer Joe Beery, who had been diagnosed with dopa-responsive dystonia but began having additional health issues that led them to get their genomes sequenced. It turned out that in addition to the dystonia, the twins also had a serotonin deficiency, for which they received treatment that they are still responding to.

Several years after these examples put clinical sequencing into the spotlight, it's clear that not every sequencing study can provide such dramatic results. But according to speakers at last week's Future of Genomic Medicine conference at the Scripps Translational Science Institute in San Diego, the approach can still provide great value for patients and their families, even in cases where it doesn't lead to a miracle cure.

The conference kicked off with an illustration of the utility of sequencing to end diagnostic odysseys, even if it doesn't provide a cut-and-dry treatment strategy. Steve and Gay Grossman provided a first-hand account of their struggles hunting down a diagnosis for their daughter Lilly, who as a baby began experiencing extreme muscle tremors at night, which gradually worsened over the years, eventually leading to muscle weakness, ataxia, food and weather sensitivity, and a host of other issues that ultimately confined her to a wheelchair. Over the course of 13 years, the Grossmans took Lilly to more than 40 doctors across the country, "with no results" other than a guess that she had some form of mitochondrial disease, Steve Grossman said at the conference.

Lilly, now 16, was accepted as the first patient in Scripps Health's IDIOM, for idiopathic disease of man, project, which was launched in 2011 with the aim of finding the root cause of rare, unknown diseases (CSN 10/19/2011). The Grossmans moved from Cleveland to San Diego in order to participate in the program.

Lilly, Steve, and Gay had their whole genomes and exomes sequenced under the IDIOM project, and the Scripps researchers ultimately narrowed the data down to two mutations: one in the DOCK3 gene, which has been associated with coordination in mouse studies, and another in the ADCY5 gene, which plays a role in dopamine signaling and motor function.

Importantly, as Gay noted at the conference, the sequencing study ruled out mitochondrial disease and signaled that Lilly would have a normal life expectancy — words, she said, that were previously "not in our vocabulary" since most children with mitochondrial disease do not survive their teenage years.

And while the genes identified in the study didn't lead to any obvious therapeutic intervention, they did inform a treatment strategy that is still a work in progress.

Jennifer Friedman, a physician at the University of California, San Diego, and Lilly's primary doctor, explained that she had already identified a list of possible treatments for episodic neurologic conditions. The normal strategy in a case like Lilly's, she said, would be to "march through" the list until finding something that worked.

However, the information about Lilly's genome helped Friedman single out one drug, a generic called acetazolimide that is used to treat a range of conditions from seizures to glaucoma to altitude sickness. Researchers at the University of Washington had identified another family with a different mutation in the ADCY5 gene, in which the affected family members shared some of Lilly’s symptoms and some responded to acetazolimide.

Friedman started Lilly on the drug and she slept through the night for 18 nights straight — the first time in 13 years that she or her parents had a full night's sleep.

Since then, however, the tremors have returned, so Friedman is looking into increasing the dosage of the drug as well as finding treatments that may have more of a biological link to the genetics that underlie Lilly's condition. Friedman noted that while the knowledge of Lilly's genome helped her select acetazolimide as the first course of treatment, that decision was not based at all on the biological mechanism of the drug.

Freidman, who also takes care of the Beery twins, stressed that Lilly's case is "very different" from the Beerys and Nic Volker. "It's very important to emphasize that though we all hope for the slam dunk, treatable condition when we do genome sequencing, the likelihood is that many things will be not as clear cut — two genes as in this case, [and] maybe no clear therapies."

Nevertheless, she said, "I think it's still very important because even though there's not a clear treatment, it provides a path forward … We don't know exactly what the future will bring, but we have — based on biology, based on experience from mouse models, other families, other patients — therapies to try and avenues to explore and I think that's very important for the future."

As for Lilly, her father noted that the outcome of the study was a success, since her "greatest fear" going into it was that the sequencing wouldn't identify anything at all.

'Another Tool Set'

Howard Jacob, who led the sequencing of Nic Volker's genome at the Medical College of Wisconsin, cited the Grossman case as an example of the importance of the "personal utility" of information from genome sequencing.

Speaking at the conference, he noted that he's often asked whether sequencing is appropriate in cases where there is no obvious course of action, but, he noted, "we do this clinically every day. We can't solve most medical diseases today. We make diagnoses all the time that we can't cure."

As an example, he cited hypertension, in which only about 25 percent of people are controlled. "Let's be honest," he said. "We have a long way to go in medicine and genomics is another tool set. It is not the answer, and in the absence of a clinical phenotype it's meaningless. But let's not pretend that it's any worse than anything else."

Similarly, in a panel discussion at the meeting, Katrina Armstrong, a professor of medicine and obstetrics and gynecology at the University of Pennsylvania, estimated that only four percent of medical decisions "have any evidence to back them up."

In that setting, she said, "any information is helpful as long as you're given the tools to understand it." While genomic data may not always lead to a "yes/no" answer, she said, "anything that gets you closer to a decision is a good idea."

Some at the conference urged caution, however. Lukas Wartman, a leukemia doctor and researcher at Washington University School of Medicine and a leukemia patient himself, had his genome and transcriptome sequenced several years ago by colleagues at Wash U, who used the information to prescribe him, off-label, the kinase inhibitor sunatinib, to which he responded (CSN 10/5/2011).

However, when asked if he thought all cancer patients should have their genomes sequenced as part of the standard of care, Wartman called for restraint — at least for now.

"Clearly we have to be very cautious about how we choose to implement this technology," he said. "I can't deny it offers tremendous potential and I think it will be incorporated into the way oncologists treat cancer patients — maybe all cancer patients — but I think that has to be built on the basis of some kind of rationally designed trials."

While patients with no other options, such as those who have relapsed or are experiencing refractory disease, "ought to seek out a center that can provide these advanced diagnostics … in terms of treating patients up front with more personalized medicine, I think that's something we really have to focus on as a research community in oncology," he said.

Meanwhile, doctors — particularly oncologists — will increasingly be faced with engaged and educated patients seeking sequencing as a medical option. Wartman noted that he hears "all the time" from his colleagues at Wash U, "who complain to me that every patient I see wants their genome sequenced." Wash U's Elaine Mardis backed this up, saying that she gets from three to five emails each week from cancer patients who have heard about Wartman's case and are seeking genome sequencing.

Likewise, Daniel Von Hoff of the Translational Genomics Research Institute, who heads up a program to sequence the genomes of late-stage cancer patients, said that he and his colleagues currently spend "at least 50 percent of our time" telling patients that their cancer is too early stage to justify sequencing.

In another panel discussion at the conference, Harvard's George Church predicted that cancer patients and parents of children with undiagnosed diseases will ultimately drive clinical sequencing to "the tipping point where it goes viral."

However, he also cautioned that the genome doesn't have all the answers. "Medical care is not about doing one modality at a time," he said. "It's all about the integration" of different types of information that doctors can interpret in order to make decisions.

Even as sequencing moves into mainstream care, it will still be just one tool among many in the clinical toolkit, said Stanford University's Atul Butte. "I don't think the genome really obviates all the rest of medicine today," he said. "It might help you to know that you should check your blood sugar a little more often, or you should get a fecal occult blood test. … If the genome helps with that, then I'd say that was [money] well spent, but that doesn't eliminate all the rest of medicine."

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