By Monica Heger
The Mayo Clinic is developing an 18-gene colon cancer panel for the Illumina Genome Analyzer with the goal of offering a single test that will be able to diagnose different subtypes of hereditary colon cancer.
The test, which the researchers are planning to launch next year, will use Agilent's SureSelect in-solution custom capture technology and will be offered to physicians as a lab-developed test with a turnaround time of between four to six weeks.
Currently, there are different tests for each subtype of hereditary colon cancer, and it is "difficult for folks to stay on top of all the tests available and where they're being offered," Matthew Ferber, co-director of clinical molecular genetics at the Mayo Clinic, told Clinical Sequencing News.
"We're trying to attain a higher diagnostic yield," he added. Currently, about 10 percent of all colon cancer cases are classified as hereditary, but an additional 15 to 20 percent are labeled "familial," and Ferber thinks there is likely an overlap between the two sets. Having one comprehensive test should help "increase our understanding of what is the overall contribution of genetics in colon cancer," he added.
Ferber and his team are currently validating the assay and will test it on between 50 and 200 patient samples, after which they plan to publish their results.
Like other pioneers in sequencing-based diagnostics, the Mayo team is grappling with questions surrounding how best to use the technology in the clinic, such as how to deal with mutations of unknown significance, how to return results to patients, and whether results need to be verified with Sanger sequencing.
The team plans to report both mutations of known significance as well as mutations of unknown significance to physicians. Ferber said that this policy is in line with guidelines published in 2007 by the American College of Medical Genetics that state that all variants — even those of unknown significance — should be reported.
"As we find the dreaded variants of undetermined significance, those will be included in the [physician's] report," he said. "That's the part where the one-on-one dialogue becomes very important."
Rather than simply return a report with a list of variants, Ferber said the Mayo team plans to engage the physician as well as a genetic counselor from the beginning of the process to help with data interpretation.
"Just listing them out isn't sufficient to aid the clinician in making decisions and understanding either the potential pathogenicity of that variant or whether or not we believe that it's benign," he said.
Other groups offering sequencing based genetic tests are also struggling with whether to report variants of unknown significance and, if so, whether to report all of them, or only ones deemed likely pathogenic.
For example, as part of a larger sequencing project to study childhood disease, the Canadian Institute of Health Research is examining the benefits and risks of returning results of unknown significance, including surveying families about their preferences (CSN 3/16/2011). Meantime, Good Start Genetics, which is planning a pre-pregnancy genetic screening test, said while it will collect data on all mutations, it will only return results with known significance (IS 9/14/2010).
Ferber noted that the US Food and Drug Administration currently does not regulate lab-developed tests, which is one reason there is not a uniform way to handle mutations of unknown significance or the interpretation of results for sequencing-based LDTs, since it is unclear what the FDA would eventually require for a test to be certified.
LDTs have traditionally been overseen by the Centers for Medicare and Medicaid Services under the Clinical Laboratory Improvement Amendments, while the FDA exercised so-called "enforcement discretion" over such tests. Last year, however, the agency signaled its intent to begin regulating LDTs, though it has not yet issued any guidance on the matter.
"We know that they want to take a more active role in LDTs and the Mayo is supportive of that role," Ferber said, "but we just don't know yet what those guidelines will be."
Similar to other sequencing-based diagnostic panels, such as the University of Iowa's deafness test and Emory University's panels for congenital disorders, the Mayo team will validate all results with Sanger sequencing (CSN 2/33/2011 and IS 5/25/2010).
"Results will not be returned back based solely on next-gen sequencing itself," said Ferber. "Most of the platforms still have a high false-positive rate, so many things show up in the data column that aren't there in the patient sample," he said.
As both the sequencing technology itself and researchers' ability to handle the interpretation improves, there will eventually be no need to validate with Sanger sequencing, he said, but for now, "at least for the smaller diagnostic panels, the loose agreement is that these things should be Sanger verified."
Ferber said that so far the response he has received from physicians has been very positive. While there has been some "apprehension about what to do with 18 genes' worth of data," he said, having a single test that will be comprehensive for all subtypes of inherited colon cancer "is very attractive to clinicians."
While a price for the test has not yet been set, and the laboratory is not involved in the pricing decisions, Ferber said that it is his goal to ensure that the panel is not more expensive than ordering three single-gene tests. "Higher than that, it really loses its value," he said.
The test will be offered through Mayo Medical Laboratories, a global reference laboratory that operates within the Mayo's department of laboratory medicine and pathology.
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