Richard Mazzarella, Ph.D.

The cost of whole-genome and exome sequencing has gone down considerably, but when will these technologies become routine?

The Human Genome Project provided a path for determining the genetic basis of many inherited diseases and neoplasms. So far, various efforts from both research institutions and private companies have yielded myriad single gene and disease panel tests for both cancer and various Mendelian diseases, which have proven quite useful in diagnosing and treating specific conditions. The scope of single gene tests is limited, making them less effective at identifying a patient’s underlying disease state and appropriate cancer drug regimens. Large cancer panels containing all the actionable genes do better at elucidating this type of information. The maturation of next-generation sequencing (NGS) technology, though, has made whole-exome and whole-genome studies viable options, especially if they can be used to assemble a mineable knowledge base that could yield a more comprehensive understanding of disease.

Currently, the cost of assessing mutations for a single gene is $300–$2,000/gene. Cancer mutation panels, the largest of which can include up to 250 genes, cost $2,000–$6,000/panel. In selecting whether to order tests, physicians must balance their emphasis and utility with economics: what information is important for diagnosis and treatment weighed against cost and what insurers will reimburse. Single-gene tests, for instance, make the most sense when physicians suspect an inherited gene as predetermining a disorder, as with autosomal dominant or X-linked diseases such as Huntington’s disease or Duchenne muscular dystrophy. Single-gene tests can also be used to determine if particular genes exist that might increase a patient’s susceptibility to disease, such as breast cancer.

Disease panels, on the other hand, can be extremely useful to verify the genetic cause of an inherited disease when clinical phenotypic evidence strongly suggests the syndrome or if the genetic risk to a familial disease has not been previously determined in a family member. But they also have limitations. The largest current cancer panel tests less than half of the genes currently associated with cancer in the COSMIC database, and a bit more than 1% of the genes in the entire human genome.  In this context, a small panel seems woefully limited, as it targets only a specific cancer type (e.g., breast or lung) and restricts potential treatments to approved drugs for the cancer type based on known genes with well-characterized mutations in a particular tissue. Larger panels can provide more options, as they can identify mutations observed across cancer types and provide therapeutic possibilities that might not have been considered if the disease were defined by tissue rather than genetics. For instance, Hagemann et al. (J. Thorac. Oncol. 2014. 9:e12-16.) recently reported a patient with a poorly differentiated thymic carcinoma who was found to have a KIT mutation, which has been shown to confer sensitivity to imatinib in gastrointestinal stromal tumors. The patient had progressed with standard chemotherapy but has had stable disease for more than one year and a marked reduction of the largest lesions upon imatinib treatment.

Larger panels are the logical course for modern treatment, as they provide a broader picture of disease. It’s only a matter of time, though, before our need for more detailed information and insights outstrips the capabilities conferred by even the largest panels. Why sequence one gene, or even 250 genes, for $2,000 to $6,000, when you can sequence and analyze a patient’s whole exome or genome for $6,000 or $7,000? Another issue that has in the past favored gene panels over whole-exome or whole-genome sequencing is coverage. The slightly higher sensitivity that can be achieved with a panel, however, is quickly being overshadowed by the ability to understand more about the genetic interactions potentially impacting a patient’s disease.

As the economics and the technology tilt the balance in favor of sequencing whole genomes and whole exomes, the question becomes when these technologies will become routine. This requires, first, for genomic testing generally to become more broadly used. Today, genomic tests are primarily developed by top-tier research institutions and delivered only to patients in nearby geographic areas or with the means to request and receive the tests. Providing easy ways for physicians in community and regional hospitals, where 80% of oncology diagnosis and treatment occurs, would in turn provide more examples of mutations, disease states, and outcomes that could be applied clinically.

Until recently, whole exome and genome sequencing at high coverage was prohibitively expensive. In addition, the analysis, storage, and management of this big data presented a logistics nightmare. While the much larger body of information garnered by sequencing the whole exome/genome will eventually yield to the identification of new cancer targets and therefore new therapies, it will also present challenges to manage and interpret. Cloud-based informatics solutions and services should reduce the infrastructure burden on hospitals. In addition, this information has the potential to assist greatly in drug development. For instance, if patient histories can be collected along with genetic information and drug regimens, this longitudinal information could assist in stratification of patients and identification of the most effective therapy according to phenotype and genotype. Such an approach would give patients the best chance of receiving effective therapies earlier, reducing costs both in therapy and testing over the hit-and-miss approach currently practiced.

The cost-effective sequencing of genomes and the broader application of genomic testing to more extensive and diverse patient populations will likely result in another 50-fold increase in genetic information relating to human disease—and this is before considering the information likely to be gleaned from RNA-Seq, which is currently primarily a research technique. It couldn’t come at a better time. As pharmaceutical companies consolidate and research budgets shrink, the increased knowledge emerging from NGS and genomics testing is vital to new drug development and the treatment and cure of cancer and other serious diseases. Large cancer gene panels provide viable therapy now, but recent advances in both technology and cost means that whole exome/genome sequencing will likely become the information platform for the therapy of tomorrow.

Richard Mazzarella, Ph.D. ([email protected]), is Chief Scientific Officer at Appistry

This article was originally published in the July 16 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this new digital publication, go to

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