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Thermo Fisher Launches Digital PCR Application to ID Drug-Metabolizing Phenotypes


NEW YORK (GenomeWeb) — Thermo Fisher Scientific has launched a new application for its Life Technologies brand QuantStudio 3D Digital PCR platform designed to enable researchers to accurately phenotype the CYP2D6 gene, a key indicator of drug metabolism.

The latest application, which is for research use only, enables researchers to perform allele-specific copy number analysis on the QuantStudio 3D Digital PCR system, and, when combined with Thermo Fisher's QuantStudio 12K Flex Real-Time PCR system, provides them with a cost-effective method to reliably characterize drug metabolism enzyme genes such as CYP2D6 — a highly polymorphic gene whose expression is implicated in metabolizing roughly 85 percent of medications through the cytochrome P450 pathway.

Thermo Fisher launched the new application at the annual meeting of the Association for Molecular Pathology last week in National Harbor, Md., where Iain Russell, senior product manager in the life sciences group at Thermo Fisher, spoke with GenomeWeb about the technology.

"The application is allele-specific copy number, and what differentiates that from copy number is we're not just determining the number of copies of a particular gene; we're breaking that down and determining the number of copies of an allele," Russell said. "You can imagine in an individual heterozygous for a particular gene, it becomes important in some applications to understand which allele has been duplicated."

Prior to its acquisition by Thermo Fisher, Life Tech first unveiled the QuantStudio 3D in 2012 at the American Society for Human Genetics annual meeting. The system features a high-density, nanofluidic silicon chip that enables the generation of up to 20,000 data points per experiment.

This architecture stands in sharp contrast to droplet-based digital PCR platforms offered by companies like Bio-Rad and RainDance Technologies, but Life Tech has maintained that its system has several advantages, chief among them is cost — the platform costs in the neighborhood of $39,000 — but also a simpler workflow, which it claims reduces the risk of sample contamination and loss of DNA that can occur in droplet-based systems.

Thermo Fisher has released several applications for the QuantStudio 3D, most recently a mutation analysis application that comprises wet-lab validated TaqMan SNP genotyping assays and an enhanced software tool to detect and quantify 40 of the most common mutations in cancer genes at a prevalence as low as 0.1 percent.

The newest digital PCR application combines TaqMan assays that are initially run on the company's QuantStudio 12K Flex Real-Time PCR system — a more expensive platform from Thermo Fisher that enables researchers to run both digital PCR and high-throughput qPCR assays on the same instrument using interchangeable blocks. These initial assays can efficiently determine the copy number of drug-metabolizing enzyme genes. Using the QuantStudio 3D, researchers can then precisely determine specific allele composition of samples with duplications in the CYP2D6 gene in less than a day.

The new application is also one of the company's first that is specific to pharmacogenomics research, where a typical clinical research customer might want to capture both genotyping and copy number information, and then classify patients in terms of their metabolism for a given drug, Russell noted.

"We've focused on CYP2D6, so in that case, as an example, an individual may have a full-function allele and a partial function allele," Russell said. "In a standard situation where they just have two copies of that gene, that would put them in a standard metabolizer area. If they have duplication of the full-function allele, then they move up into an ultra-metabolizer category. And that's a very different treatment management for that classification versus someone who's in a lower category."

Russell cited the drug codeine as a real-world example. Codeine is broken down in the body into its active form, morphine. An ultra-high metabolizer who is administered codeine might experience toxicity, something physicians want to be cognizant of.

"If I'm in a lower category … then it's a standard treatment process – I would adjust my dosage based upon age, upon weight, that type of thing," Russell said. "If I'm in the lowest category, then I actually don't have enough enzyme activity there to create that active form, to break codeine down to morphine. So there are particular heterozygous genotypes or diplotypes associated with individuals who also have a duplication at the CYP2D6 allele that would [change] their metabolizer phenotype, and … who could be miscategorized as a result of just the copy number and the genotyping information."

This level of information is simply not currently provided by labs conducting pharmacogenomic testing, Russell said, and previously could only be obtained using next-generation sequencing. "We've been hearing from some of our customers that this is a particular instance where they would like to be able to provide a more accurate estimation of what the metabolism level for that particular patient actually is," he added.

Thermo Fisher is hoping that clinical researchers will use the new application to conduct retrospective studies of drug metabolism to build evidence for potential clinical implementation of such an assay. However, Russell stopped short of saying that the company might develop the test for clinical use.

"We'll see first what the response is from that customer segment," he said.

In general, Russell noted, digital PCR is a "very nascent technology, and what we've seen with all of these technologies is they go through research use, and at some point when the clinical utility is high enough, there is a pull into the clinical segment. I think it will take some time for it to get there."