One of the leaders in cell-free DNA testing, Natera, a worldwide genetic testing and diagnostics company that?s changing how doctors and patients manage genetic disease, plans to commercialize a research-use-only service for whole exome sequencing of circulating tumor DNA, using plasma samples from patients with cancer.
Whole exome sequencing is a genomic technique for sequencing all of the protein-coding region of genes in a genome (known as the exome). The process consists of two steps
- The first step is to select only the subset of DNA that encodes proteins. These regions are known as exons ? humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs;
- The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.
The goal of whole exome sequencing is to identify genetic variants that alter protein sequences, and to do this at a much lower cost than whole-genome sequencing.
Natera’s new service, called Signatera? RUO, is the first circulating tumor DNA (ctDNA) assay custom-built for treatment monitoring and minimal residual disease (MRD) assessment. The methodology identifies 16 unique, clonal, somatic variants individualized to each patient?s tumor, followed by multiplex Polymerase Chain Reaction (PCR) and ultra-deep sequencing for longitudinal ctDNA analysis of whole blood samples.  According to company representatives, the pan-tumor potential of Natera’s Signatera test has been demonstrated across several tumor types, including lung, colorectal, bladder, and breast.
Natera’s Signatera? RUO available for research purposes alone, which represents the a next advancement in company’s innovative oncology ctDNA program.
A clinical version is expected to be available in the second half of 2019.
The assay does not require tumor tissue and will interrogate approximately 20,000 genes from ctDNA to detect somatic mutations, representing a significant increase in coverage over most commercially available fixed liquid biopsy panels.
There are multiple benefits to the new plasma exome sequencing offering, including the ability to design assays when tissue is not available. The assay may also allow researchers to characterize resistance mutations, actionable mutations, neoantigens, and tumor evolution. One of the key benefits of the new product offering is the capability of generating valuable new data about tumor evolution over time.
The plasma exome service can be ordered as a stand-alone assay, or reflexively for ctDNA-positive cases. Many researchers want a comprehensive view of tumor evolution in order to link to treatments and outcomes, but it is very expensive to conduct a comprehensive analysis in early-stage or adjuvant disease, where tumor DNA is often not detectable in the plasma. With the combined service, researchers can first use Natera’s Signatera to monitor patients for the presence or absence of ctDNA, and for positive patients they can reflex to a plasma exome to characterize tumor evolution using the same exact DNA library sample.
The first of multiple publications has been accepted in a top peer-reviewed journal and is expected to be published this quarter. Initial data has shown concordance between whole exome sequencing from tissue and plasma, and also strong concordance between whole exome sequencing and Natera’s Signatera.
“This exciting capability grows out of our deep molecular and bioinformatics expertise, and optimized sample and library preparation methods which consistently deliver a high yield of cell-free DNA molecules,” said Bernhard Zimmermann, Natera’s Vice President for Research and Development.
“This expertise will enable multiple new research applications in oncology,” Zimmerman added.
“The plasma exome capability adds an important component to our suite of services for cancer researchers,” said Eric Lindquist, Natera’s Vice President Oncology Business Development.
“We are pleased with the significant momentum in our pharma business and believe we are on track to achieve our goal of $40 to $50 million in cumulative contracted value. Our combined offerings enable us to access the approximately US$ 21 billion ctDNA molecular residual disease and liquid biopsy market in a very competitive manner,” Lindquist concluded.
The Signatera? RUO test was developed by Natera, a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). The test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the U.S., certification of the laboratory is required under CLIA to ensure the quality and validity of the tests.
 Sethi H, Salari R, Navarro S, et al. Analytical validation of the Signatera? RUO assay, a highly sensitive patient-specific multiplex PCR NGS-based noninvasive cancer recurrence detection and therapy monitoring assay. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting; April 17, 2018; Chicago, IL. Abstract 4542.
 Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017;545(7655):446-451
 Reinert T, Henriksen TV, Rasmussen MH, et al. Personalized circulating tumor DNA analysis to monitor colorectal cancer. Poster presented at: American Association for Cancer Research Annual Meeting; April 17, 2018; Chicago, IL. Abstract 1590.
 Birkenkamp-Demtr?der K, Christensen E, Sharma S, et al. Sequencing of plasma cfDNA from patients with locally advanced bladder cancer for surveillance and therapeutic efficacy monitoring. Poster presented at: American Association for Cancer Research Annual Meeting; April 17, 2018; Chicago, IL. Abstract 3653.
 Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC ? challenges to implementing ctDNA-based screening and MRD detection [published online ahead of print July 3, 2018]. Nat Rev Clin Oncol. 2018;15(9):577-586. doi:10.1038/s41571-018-0058-3.
Last Editorial Review: April 10, 2019
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