SAN DIEGO (GenomeWeb News) – Genomic information is already having an impact on medical practice, and advances in technologies such as next-generation sequencing will only accelerate the advance of genomic medicine, according to speakers at a conference here this week.
However, speakers at the Future of Genomic Medicine conference, co-organized by the Scripps Translational Science Institute and the J. Craig Venter Institute, tempered this enthusiasm by highlighting a number of obstacles standing in the way of making whole-genome studies a standard part of medical care.
Not least of these challenges is the fact that physicians are uncertain about how to use genomic information in practice. During a panel discussion on personal genomics and other emerging trends, an attendee who identified himself as a practicing physician noted that while he is enthusiastic about the field, he fears that "human nature" will play a large role in determining how patients put genomic information to use — raising the question of how much influence doctors will even have in guiding treatment based on genomic knowledge.
As an example, he said that many of his patients don't follow his advice to get screened for breast cancer even when there is a clear family history of the disease, while others have opted for prophylactic double mastectomies based on a BRCA test.
"I'm on the front lines of this and I'm scared," he said.
Another physician in attendance, commenting during a different panel discussion, noted that his priority is diagnosis and treatment of disease, "So what is the benefit of sequencing an entire human genome?"
In response, David Bentley, vice president and chief scientist at Illumina, said that a whole-genome scan would give a patient "one set of information for their entire lifetime," which could point toward disease risks that might determine how often a patient should be screened for particular diseases during his lifetime, for example. Nevertheless, he acknowledged that the use of that genomic information "is a different matter" because knowledge of the role of genes in disease is still limited, and not every SNP is informative.
Indeed, many speakers at the conference noted that while genome-wide association studies have provided a wealth of knowledge about SNPs and other variants that may be implicated in disease, there are still a number of limitations to that approach that have left large holes in the current knowledgebase.
For example, Sarah Murray, director of genetics at Scripps Genomic Medicine, noted that most GWAS papers have concentrated on European populations, so their results may not apply to other ethnicities in clinical practice. In addition, she noted that most of the GWA studies published to date have used a case-control study design, which does not capture information about patterns of disease onset. An alternative, she said, would be to perform GWAS as part of a longitudinal study that would track patients over the course of many decades.
Murray explained that Scripps is partnering with Tulane University to genotype 1,200 samples from the Bogalusa Heart Study, which began following a large cohort of children in the 1970s when they were between the ages of 5 and 17. The goal of the GWAS is to identify SNPs and haplotypes associated with cardiovascular disease risk profiles, she said. So far, the project has already found a variation associated with a change in triglyceride levels over time.
Several speakers noted that the availability of GWAS data has also called into question the "common disease, common variant" hypothesis, which holds that complex diseases are probably due to the cumulative effects of many different common variants acting in concert. But in most GWA studies, common variants — those found in more than 5 percent of the population — only account for a very small fraction of the estimated heritability of these diseases.
In light of these results, said Kelly Frazer, director of genomic biology at Scripps Genomic Medicine, rare, "high-penetrance" variants "may play an important role in phenotype," which means that a great deal of follow-up work must be done to identify these players.
Another area where knowledge is still lacking is genomic structural variation. Stephen Scherer, senior scientist at the Hospital for Sick Children, said that in terms of bases, copy number variants account for far more variation in the human genome than SNPs, but the field is still in its earliest days in terms of discovery.
Scherer said that one challenge for CNV discovery is that the "technology is still imperfect." For example, he said that his team ran a sample of Craig Venter's genome on the Affymetrix and Illumina platforms, using several different software packages for each platform, and got different CNV calls every time. In addition, he said, the longer a CNV is, the more difficult it is to detect.
Scherer and others pointed to next-generation sequencing as a promising technology for identifying CNVs and other genomic features that other platforms cannot: "I think sequencing will be the ultimate form of genotyping," Scherer said.
But most were quick to point out that second-gen sequencing platforms have their limitations as well. Samuel Levy, director of human genomics at JCVI, said that the current technologies "are not yet generating sequencing data that can readily be assembled into diploid genomes," and noted that he and others at JCVI "think that may be an issue."
Richard Gibbs, director of the Human Genome Sequencing Center at Baylor College of Medicine, agreed, noting that there is "some way to go before we get the completeness and accuracy we need for genomic testing," and that "a lot of work needs to be done to make [sequencing technology] useful for physicians."
But despite these challenges, most speakers were optimistic that the future of genomic medicine is not that far off, and some argued that the recent rise of direct-to-consumer genetic testing is a sign that the era of genomic medicine has already begun.
Eric Topol, director of the Scripps Translational Science Institute and a co-organizer of the conference, noted that because of DTC genomic testing, "physicians might be prodded by consumers" to learn more about SNPs and disease associations.
Topol cautioned that there are still many questions surrounding personal genomics, and outlined the Scripps Genomics Health Initiative — a collaboration with Navigenics and Microsoft to determine the long-term behavioral effects of personal genetic testing that kicked off last fall.
The first 3,300 participants in the program, which hopes to enroll up to 10,000 people in the Scripps Health System, are scheduled to get their results on Monday, Topol said.
In response to a question about whether consumer genomics firms are "exploiting patients" because the results of their genome scans cannot be used to guide medical treatment, Topol was quick to note that Scripps is conducting the study to help address such questions. "If we find it has no value, we'll be the first to publish that," he said.
On the other hand, he noted, given that thousands of people are already using these services, "it would be unethical not to look into it."