New wtRNA-seq test detects fusions in 1,445 genes with high accuracy, improving cancer diagnosis, treatment decisions, and clinical trial eligibility.
Mayo Clinic Laboratories has introduced an innovative whole transcriptome RNA sequencing assay (wtRNA-seq) that can detect gene fusions in 1,445 genes across a wide range of solid tumors, including central nervous system (CNS), bone, and soft tissue tumors, helping to refine diagnosis and guide more targeted treatment.
The new assay (Mayo ID: MCRSP) is highly informative and is expected to frequently refine — and in some cases significantly change — diagnoses and help guide treatment decisions, including eligibility for clinical trials. When integrated with DNA sequencing in a single workflow, it offers a meaningful advantage for precision oncology testing.
“This will be the most comprehensive test on the market and is designed to remain relevant for years to come,” says Kevin Halling, M.D., Ph.D., co-director of the Clinical Genomics Laboratory at Mayo Clinic. “In addition to expanding coverage by more than 1,000 genes beyond our former 138-gene SARCP assay, we've enhanced the design of the assay by incorporating a large number of additional probes to better capture underrepresented regions of the transcriptome in commercial kits. Together, these improvements strengthen our ability to detect challenging fusions.”
The test was needed because current targeted gene fusion assays for sarcomas and brain tumors were missing relevant genes. Although its main utility is for sarcomas and brain tumors, the test can be used for multiple cancer types, such as salivary gland tumors, lung cancers, and other tumor types known to have clinically relevant fusions.
“This will be the most comprehensive test on the market and is designed to remain relevant for years to come."
Kevin Halling, M.D., Ph.D.
Gene fusion detection in RNA versus DNA sequencing
Hussam Al Kateb, Ph.D., who co-directs the Clinical Genomics Laboratory with Dr. Halling, explains the advantages of RNA sequencing over DNA sequencing.
“Although there are some complementarities between the two approaches — for example, some fusions may be detectable only in DNA or only in RNA — RNA-based fusion detection is generally more efficient and more accurate,” says Dr. Al Kateb. “One major reason for that is that fusion points often occur within large introns, which can be difficult to capture using short-read DNA sequencing. In contrast, RNA undergoes splicing, and this event removes intronic regions and leaves behind short, clean exon-exon junctions that make fusions easier to identify with high confidence.”
Another advantage of RNA sequencing is its ability to detect new gene fusions and novel breakpoints involving unknown fusion partners, which continue to be discovered on a frequent basis. DNA-based methodologies, by comparison, often rely on targeted capture of known breakpoint regions, limiting their ability to identify unexpected rearrangements.
Better sensitivity
The new wtRNA-seq assay will also increase sensitivity in detecting fusions as compared to targeted tests.
Dr. Halling explains, “If you compare our test to our former SARCP and NEUFUS tests, which have about 100 genes on each of those, if you did a head-to-head comparison, we should increase the sensitivity because we're covering every last exon of those genes, whereas the current assays just target certain exons. In addition, we're going to see an increase in sensitivity because we have increased gene content by at least tenfold on this panel compared to the current panels.”
On the technical side, the whole transcriptome RNA-seq test has 99% sensitivity and 96% specificity with an overall accuracy of 98%.
Answers that help guide treatment decisions
This new assay (Mayo ID: MCRSP) is highly informative and is expected to frequently refine — and in some cases significantly change — diagnoses and help guide treatment decisions, including eligibility for clinical trials. When integrated with DNA sequencing in a single workflow, it offers a meaningful advantage for precision oncology testing.
A comprehensive approach: DNA mutational analysis combined with RNA sequencing
In addition to offering whole-transcriptome RNA sequencing as a stand-alone test, Mayo Clinic Laboratories has also upgraded its targeted sarcoma and neuro-oncology DNA next-generation sequencing panels, which previously included smaller RNA sequencing components.
“These panels now incorporate whole-transcriptome RNA sequencing with 1,445 reportable genes,” says Dr. Halling. “The updated offerings include the Mayo Complete Sarcoma Panel (Mayo ID: MCSRC), which features DNA mutation analysis across 31 sarcoma-related genes, and the Neuro-Oncology Panel (Mayo ID: NONCP), which includes DNA mutation analysis across 87 genes associated with neurologic tumors.”
Comprehensive testing should include both RNA and DNA sequencing. Used together, these approaches reveal more information than targeted assays alone, increasing diagnostic yield and providing a clearer, more complete picture of the tumor.
Dr. Halling continues, “The two tests are complementary. In many cases, the DNA testing will identify mutations that are diagnostically or therapeutically useful that RNA-seq does not identify. Additionally, for fusion-positive tumors such as Ewing sarcoma with an EWSR1:FLI1 fusion, DNA testing may find additional alterations that may have clinical significance, for example, P53 mutations, which would have additional prognostic significance.
“The DNA plus RNA sequencing approach aligns with updated guidelines for integrated molecular reporting established by the World Health Organization and the National Comprehensive Cancer Network, and also the College of American Pathologists.”
Dr. Al Kateb summarizes wtRNA-seq this way:
“I would say this is a test that can identify rare, novel, or unexpected fusions that might be missed by targeted panels,” he says. “It also can be applied to multiple tumor types without needing to redesign the assay for each new fusion. This is particularly valuable in rare and unusual tumors where the expected fusions may not be well defined. And finally, it can help identify actionable fusions that can guide diagnosis and prognosis of the disease in addition to targeted therapy selection and clinical trials enrollment.”
“I would say this is a test that can identify rare, novel, or unexpected fusions that might be missed by targeted panels."
Hussam Al Kateb, Ph.D.
Of course, the most important value of this test is how it will help patients.
“We're very excited about this test offering because we know it's going to improve patient care,” says Dr. Halling. “And that's what we get excited about doing every day.”
