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Apr 1, 2014 (Vol. 34, No. 7)

Clinical Genomics Transcends Sequencing

  • Challenges in Clinical Genomics

    Click Image To Enlarge +
    Carpe Novo, an in-house informatics tool at the Medical College of Wisconsin, was used to analyze more than 4,000,000 variants identified via WGS. Each variant is shown with a specific color and shape according to likely impact. The red, multipointed variants are the most likely to alter the function of the underlying protein. Some of these are likely to be the molecular changes responsible for disease in this patient.

    Elizabeth Worthey, Ph.D., a director in the Genomic Medicine Clinic at the Medical College of Wisconsin and Children’s Hospital of Wisconsin, shares Dr. Jongbloed’s opinion that WGS is preferable to exome sequencing in general. “If you focus on the exome, nongenic regions aren’t covered. Also, the first exon and some parts of other exons of a gene are often not covered very well.” She also sees challenges in sequencing regions with high GC content and in designing probes for regions that are homologous to other regions of the genome.

    “If finances weren’t an issue, everyone would do WGS,” Dr. Worthey says. “In some cases, clinics may resort to using WGS as a reflex test for exome sequencing. If the answer isn’t there, you go to WGS.” Regardless, Dr. Worthey remains optimistic that costs will come down as technology improves.

    The Genomic Medicine clinic sees about 20 to 25 new patients each month and performs WGS for about one-third to one-half of them. The current cost is about $5,000 per patient for clinical exome sequencing and analysis, and it is about $17,000 per patient for WGS. “The costs will definitely come down for WGS. For example, the recently released Illumina HiSeq X Ten systems will provide individual centers with two or three times the capacity of what the largest centers in the world can currently process combined.”

    Dr. Worthey sees the greatest challenge for clinical genomics in the interpretation phase. “People say that while the sequencing costs $5,000, the analysis costs $1 million. But that needn’t be true—not if the lab has a suitable clinical analysis tool in place.”

    The area that needs improvement the most is clinical interpretation, explains Dr. Worthey: “For example, how do you differentiate between all these errors, polymorphisms, causal mutations, etc.? One way is to determine whether a variant has been identified as deleterious previously, or whether it has been seen in many different individuals with different clinical presentations.”

    Dr. Worthey points out that there are lots of repositories where this type of data is maintained. “If somebody else has found the same mutation in a patient elsewhere, then that’s what you are looking for, but you won’t know if you don’t have access to their data.”

    Ultimately, Dr. Worthey surmises, the problem is data sharing: “If you have been working on breast cancer for many years, are you going to want to put your data in someone else’s database? Ideally, we would develop something where we could share data instantaneously, or there would be a central repository where we could access the data.” But such a repository, adds Dr. Worthey, “would have to be updated frequently for the greatest impact.”

    WGS results cannot be interpreted effectively, Dr. Worthey suggests, unless they are compared with all clinical data available from affected patients as well as those who may have the same disease in an early or unusual presentation: “Clinical presentation data can be one page or many hundreds of pages, and there will have to be efforts to better catalogue and curate the data for others to interpret it successfully.”

  • Quality Issues

    A major challenge for any diagnostic laboratory is ensuring that the data is correctly matched with the original sample and patient. For clinical genomics, this is particularly important, since samples change hands several times.

    The tissue could be isolated in a hospital and sent to a separate core facility for nucleic acid isolation and sequencing, and the sequence could be analyzed and interpreted offsite by a bioinformatics team. Thus, a unique genetic label that can be assigned at the time of isolation and tracked at each stage of this process is highly desirable.

    Sarah Ennis, Ph.D., head of genomic informatics at the University of Southampton, U.K., has identified 117 unique SNPs for the approximately 180,000 exons in the human genome. The SNPs that Dr. Ennis and her colleagues have identified are sufficiently varied that there is little chance that two individuals in a population of 100,000 could have the same SNP fingerprint. Still, Dr. Ennis notes that there is a somewhat higher frequency of such duplicates in the Han Chinese population (1 in 85,000).

    While annotating the SNP data is challenging, perhaps the greatest obstacle in controlling data quality is communication. “We need multidisciplinary teams working together and discussing things, rather than working in silos,” remarks Dr. Ennis. “Also, we need to develop more and better wet lab functional models for genomic data. It’s very hard to just look at a histopathology report and pull out an answer.”

  • Interpreting Genomic Data

    Although NGS has been available to scientists at large research institutions for some time, it did not enter the clinic until recently. Steve Lincoln, senior vice president at Invitae, a San Francisco-based company that develops genetic diagnostics, believes that the clinic represents not only an opportunity to increase the usefulness of genetic testing, but also the chance to reduce its costs.

    “The biggest difference between clinical and research sequencing is how the data are interpreted. Many groups know how to do sequencing, and the platform—exome, panels, or whole genome—is not necessarily the biggest differentiator,” says Lincoln. “What matters is that the results are made understandable and actionable to doctors, and Invitae has developed tools to facilitate this.”

    Laboratories must handle data interpretation, asserts Lincoln, because doctors need to focus on counseling each patient and making treatment decisions. If laboratories are to satisfy doctors, they will have to upgrade their capabilities: “There are increased costs in clinical versus research sequencing in order to deliver this diagnostic quality data that will inform decisions such as chemotherapy or surgery.”

    “There has been a steady stream of improvement in the 25 years I have worked in this field,” Lincoln observes. “This will only continue and lead to an increase in quality over the next few years. During the same period, there will also be an increase in awareness of how to use genetic information in more ways that will benefit patients.”

    Lincoln and Invitae are also big proponents of data sharing through a centralized repository. “Not only do we support it, we are helping to build it. Our business will succeed because we can deliver high-quality, actionable results based on widely accepted medical and scientific knowledge.”

  • Check Back in a Few Years

    Lincoln says a better question to ask iswhat clinical genomics will look like in five years or even three. Current debates might focus on the benefits of WGS versus exome sequencing.

    It is certain, however, that both NGS technologies and the management of data will only improve in the near future. The nature of this data will encourage scientists and physicians to work together across disciplines to provide easily interpretable results in the clinic.



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