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Next-Gen Sequencing Makes Inroads into Clinical Applications in 2010

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By Monica Heger

While there were a number of advances in next-generation sequencing platforms in 2010, perhaps the most important trend in the market was the realization of a number of clinical applications for the technology. The use of sequencing in disease research for both Mendelian and complex diseases continued to advance during the year, but 2010 also saw the launch of several sequencing-based diagnostic tests, as well as pharmaceutical companies entering the sequencing field and the first examples of sequencing being used to make decisions on patient treatment.

While great strides have been made, hurdles still remain before whole-genome sequencing can be fully adopted by clinicians. For example, Stanford bioengineer and Helicos co-founder Stephen Quake had his genome — which had been sequenced in 2009 on the Heliscope — clinically annotated early in the year, revealing the plethora of challenges in introducing whole-genome sequencing to the clinic (IS 5/4/2010).

One of the major challenges going forward will be how to analyze and make sense of the enormous amount of data generated from a whole-genome sequence. Translating that data into predictions of disease risk is proving to be a huge undertaking, as demonstrated by the Quake analysis, which took months and included more than 30 authors.

Nevertheless, researchers have continued to move forward, and have made inroads into using sequencing beyond pure research and into the clinical setting.

From Mendelian to Complex Diseases

In the fall of 2009, the first example of using exome sequencing to pinpoint the causative mutation in a Mendelian disease was published — a study that sequenced the exomes of four affected individuals to identify the disease gene in Miller syndrome. Since then, both exome and whole-genome sequencing have proven useful for pinpointing disease genes in a number of other Mendelian diseases, such as Joubert syndrome and Charcot-Marie-Tooth disease; and this past year researchers also made advances using sequencing to study more complex diseases such as cardiovascular disease, autism, and cancer.

In October, researchers at the Broad Institute identified the gene responsible for familial hypolipidemia — a simple subset of a complex disease — with exome sequencing (IS 10/19/2010). National Institutes of Health researchers also began using next-gen sequencing in their ClinSeq project to identify the causative genes in atherosclerosis (IS 6/8/2010). The NIH also launched a program in 2010 to use exome sequencing to help identify rare, undiagnosed diseases in patients. As of November, the researchers had sequenced 50 exomes of 11 patients with unknown diseases and their family members, as well as the whole genomes of three patients, finding disease causing variants in two patients, and variants likely to be disease causing in two other patients (IS 11/30/2010).

Additionally, a group from the University of Washington has been using exome sequencing to study complex diseases, and in October presented unpublished results from a study of sporadic autism, in which they identified a number of promising candidate variants.

Perhaps no disease is as genetically complex as cancer, and as recently as this past spring, some researchers were questioning the clinical utility of sequencing cancer genomes, citing the inability of sequencing to identify recurrent mutations in some of the first cancer genomes sequenced (IS 3/23/2010).

However, since then, much more headway has been made. Researchers from Washington University's Genome Center, who sequenced the first cancer genome, are now sequencing tumors from breast cancer patients enrolled in a clinical trial of hormone therapy in order to identify patients who will respond to treatment based on their molecular profile (IS 8/10/2010).

Additionally, groups have also made use of transcriptome and other targeted sequencing of cancer genomes to specifically look for mutations that will make good drug targets, including a group from the University of Michigan that identified druggable targets in prostate, gastric, and skin cancer (IS 6/8/2010).

And in one of the first demonstrations of its kind, a team from the BC Cancer Agency used transcriptome sequencing in conjunction with whole-genome sequencing of a patient with a rare form of tongue carcinoma to help determine the best course of treatment (IS 9/28/2010).
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Diagnostic Tests Take Off

The past year also saw the development of numerous sequencing-based diagnostic tests by companies and research organizations for diseases ranging from X-linked mental retardation, hypertrophic cardiomyopathy, epilepsy, and mitochondrial diseases. Emory University, Ambry Genetics, and German sequencing service provider Center for Genomics and Transcriptomics were among those to launch diagnostic tests this year (IS 5/25/2010 and 10/26/2010).

Even Genomic Health, which markets a portfolio of tests based on real-time PCR such as its Oncotype DX breast cancer test, has jumped on the sequencing bandwagon. This year, it said that it expects all of its tests to eventually be based on sequencing, and plans to first use the technology for biomarker discovery in clinical cancer samples (IS 8/31/2010).

The tests released this year all employ the use of targeted next-gen sequencing of upwards of 100 genes and typically cost in the range of several thousand dollars.

There has been some debate as to whether this targeted sequencing approach is a good way of developing sequencing-based diagnostics, given the falling price of whole-genome sequencing. Some researchers have questioned the viability of selling tests for upwards of $5,000 when the $1,000 genome seems so imminent. However, mainly because of the complexities involved with interpreting the data from whole genomes, companies and clinicians are embracing the more targeted approaches for diagnostics for the time being.

Furthermore, headway has been made in using sequencing as a pre-pregnancy screen to establish carrier status for numerous genetic diseases. In the fall, Ambry launched its AmbryScreen, which tests for 75 childhood conditions for $450.

Additionally, the National Center for Genome Resources and Good Start Genetics are also developing pre-pregnancy tests, which they plan to launch in 2011 (IS 9/14/2010). These tests will also likely fall in the $300 to $500 price range.

Finally, Sequenom remains poised to be the first to offer a non-invasive sequencing-based fetal diagnostic test. This past year, the company completed its technical validation for a Down syndrome test on the Illumina HiSeq 2000, and this month it will begin the clinical validation process (see related story, this issue). The company expects to launch the test in 2011.

Opening the door for the development of additional non-invasive fetal diagnostics tests, researchers from the Chinese University of Hong Kong, who also collaborated with Sequenom on the company's Down syndrome test, demonstrated that the entire fetal genome could be identified from maternal plasma (IS 12/14/2010). While the method developed by the team is currently too expensive to employ on a genome-wide scale, as with other sequencing-based diagnostic tests, a targeted approach testing for specific diseases will likely be the first commercial application.

Big Pharma Embraces Sequencing

In a sign that industry also sees sequencing's potential in clinical applications, large pharmaceutical companies including Merck, Johnson & Johnson, GlaxoSmithKline, and Pfizer have begun to use next-gen sequencing for drug development, biomarker studies, and to identify patients for clinical trials (IS 8/10/2010 and 9/7/2010).

The companies, which reported preliminary results of their sequencing studies at last summer's Next Generation Sequencing and Genomic Medicine Summit in Burlingame, Calif., all think that whole-genome sequencing is still too costly for clinical applications and are instead using more targeted approaches.

Johnson & Johnson is using a targeted sequencing approach to search for new drug targets in known oncogenes. Similarly, Pfizer is using targeted sequencing to look for drug targets in tumor samples.

GSK, meantime, is using targeted sequencing to look for variants — ideally those for which the company already has already developed drugs — in cardiovascular, respiratory, psychological, immune, and neurodegenerative diseases. Merck is focused on transcriptome sequencing of schizophrenia patients.

While the ultimate goal of genome sequencing — the ability to sequence everyone's genome for use in risk prediction and treatment decisions — is still a long-term prospect, 2010 witnessed the advance of a number of developments in the clinical arena that serve as a promising sign that the field is making progress toward that aim.


Have topics you'd like to see covered by In Sequence? Contact the editor at mheger [at] genomeweb [.] com.

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