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Whole-Genome DNA Sequencing

May 2011

The GENE-ie is out of the bottle…are we headed toward a new “information age” in molecular diagnostics?

High Aspirations
Since completion of the human genome project in 2003, the “Holy Grail” has been to reduce the time and cost associated with sequencing a genome to the point at which it becomes commonplace in medical care. Viewing $1,000 as a critical cost threshold, the J. Craig Venter Science Foundation announced in 2003 a $500,000 prize that would be awarded to the group whose technology achieved this ideal. In 2006, the X PRIZE Foundation added a $10M incentive to the race.¹

Prizes and current cost constraints aside, several recent publications in the medical literature already highlight the power that whole genome sequencing offers for patients with diseases that defy all other attempts at diagnosis and choice of therapy (see below). These early examples may represent merely the tip of the iceberg if ongoing advances remain on course, potentially leading to new models of molecular diagnostic product development and commercialization.

Not Science Fiction Any More….
While the $1,000 genome is not immediately imminent, the pace of progress, driven by ongoing evolution of multiple “next generation sequencing” (NGS) technology platforms, suggests that increasing clinical use of individual genome sequence data is likely within the next several years.

A number of observations bode well for continued progress:

• Continued Reduction in Costs: In the past 2 years, DNA sequencing costs have decreased >10-fold, and over the past 3 years, the reduction has been more than 100-fold.² Illumina recently announced that its list price for sequencing whole human genomes through the Illumnina Genome Network now ranges from $4,000 to $5,000 per sample for batches of 10+ or 50+ samples, respectively.³

• Early Clinical Adoption of NGS Technology: In 2008, GeneDx (a commercial reference laboratory) pioneered the clinical use of “next generation” DNA sequencing technology in its multi-gene test for Hypertrophic Cardiomyopathy.⁴ Since then, a number of other NGS-based multi-gene tests have become available at Gene Dx as well as several academic laboratories. While these tests do not involve whole-genome sequencing, they represent a significant advance over what was feasible with traditional Sanger DNA sequencing, and begin to lay the early foundation for clinical adoption of NGS.

• Recent Success Stories: Several recent publications have highlighted the power that whole genome sequencing offers for patients with diseases that defy all other attempts at diagnosis.

  • In a report published in the April 11 issue of JAMA⁵, whole genome sequencing revealed a novel cancer susceptibility mutation in a patient with early onset of multiple tumors. Although this did not save the patient’s life, it has life-saving implications for her children who may have inherited the mutation.

  • A second April 11 JAMA article⁶ describes the use of whole genome sequencing to resolve contradictory clinical and cytogenetic findings in a patient with acute myeloid leukemia. A novel translocation that could not have been identified with classic cytogenetic testing was found, and led to a change in therapy.

  • In the March issue of Genetics in Medicine⁷, a case is described in which whole exome (functional genome regions) sequencing lead to diagnosis and treatment of a child with a life-threatening but previously undefined form of inflammatory bowel disease.

While these early indicators are encouraging, many practical issues certainly remain, including sample size/preparation requirements, clinical laboratory logistics, validation in the clinical setting, implementation into clinical practice, cost of current platforms, regulatory and reimbursement considerations. In addition, one of the most fundamental challenges is managing, processing, interpreting and appropriately reporting the data.

"Leap Frogging" Over Other Technologies/Tests
Remaining challenges notwithstanding, the breadth and depth of data capture by NGS technologies could enable them at some point to ‘leap frog’ beyond a number of other technologies whose outputs would become both redundant. While the actual disruptive potential of NGS remains to be seen, it could in theory displace a number of tests/technologies such as:

• Single nucleotide polymorphism (SNP) or mutation tests (mass spectrometry, allele-specific PCR-based assays, microarray platforms)

• DNA methylation detection

• Gene expression profiling (microarray platforms, RT-PCR, other approaches)

• Cytogenetic tests (FISH, comparative genomic hybridization)

This possibility should be carefully considered in any longer-term diagnostic or companion diagnostic development plan, or technology assessment.

Information Overload
The analysis of whole-genome DNA sequencing data can challenge even the bioinformatics experts themselves, let alone translational researchers and clinicians seeking to correlate DNA sequence variation with disease or response to therapy⁸. There is a gap to be closed between advances in sequencing capacity and evolution of bioinformatics solutions in order to ensure that the $1,000 genome does not carry a $10,000+ price tag for data analysis. However, within this challenge lies an opportunity for novel solutions.

After initial data analysis, comes the task of assigning clinical significance. While this is easy for specific variations with known disease association, the data set will also include variations of unknown significance. These could represent novel pathogenic variants or benign variations. Thus, some genetic variations will provide clear diagnostic, prognostic or predictive information that drives treatment decisions, some will inform reasonable diagnostic hypotheses, and others will await further research.

Information as the New Product
In addition to data that is immediately actionable, whole genome (or exome) sequencing will also generate extensive data that will be latent until either: (i) new queries are made of this data based on future clinical needs/observations for an individual patient; or (ii) future research assigns clinical significance to previously uncharacterized genetic variations. The gradual accumulation of such patient-specific ‘reservoirs’ of genetic information could forever change the definition of a molecular diagnostic product….the new “product” would become clinical data correlating previously uncharacterized genetic variation with disease and/or response to therapy. Future tests could be virtual in nature, based on simple queries of an individual’s existing genome sequence data. If this scenario plays out, it raises fundamental questions regarding product development and commercial models – what would be the best ways to create, protect, and deliver value in such an environment?

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About the author: Rob Pogulis is a Principal at the Frankel Group. To contact him regarding this post, email blog@frankelgroup.com.

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1: Science 311:1544-1546 (2006)
2: www.genome.gov/sequencingcosts. Accessed [05/13/2011]
3: Illumina, Inc. Press Release (Illumina Reduces Price of Whole Genome Sequencing Through Illumina Genome Network) 05/09/2011
4: BioReference Laboratories, Inc. Press Release (BioReference Laboratories, Inc. Announces NextGen Sequencing for Dilated Cardiomyopathy (DCM) Testing) 04/07/2009; www.genedx.com
5: JAMA 305:1568-1576 (2011)
6: JAMA 305: 1577-1584 (2011)
7: Genet Med 13:255-262 (2011)
8: Nature Meth Suppl 6:S2-S5 (2009)