DNA sequence with colored letters on black background containing mutation
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Ambry Genetics has announced findings from a large-scale study that showed paired RNA and DNA genetic testing detected elusive pathogenic variants in 1 of every 950 patients that were missed by DNA testing alone. The findings, were published in Genomic Medicine.

The researchers say that concurrent RNA and DNA testing helps identify more patients at risk by determining if an uncertain result from DNA testing is normal or disease-causing, and expands the range of genetic testing to identify mutations that DNA-only testing misses.

“With our +RNAinsight test we were the first company to offer upfront paired DNA and RNA sequencing to give clinicians and their patients the most accurate and comprehensive information about their cancer risk,” said Tom Schoenherr, CEO, Ambry Genetics. “This study confirms that conducting RNA and DNA testing together is critical to help identify high-risk individuals who would have been missed by DNA-only testing.”

According to the National Library of Medicine, as of August 2017, there were approximately 75,000 genetic tests on the market, representing 10,000 unique test types. Many of these DNA-only tests exclude large portions of DNA such as introns, a sequence of DNA spliced out before an RNA molecule is translated into a protein. In addition to omitting large portions of introns, DNA-only testing lacks the functional context to determine whether a variant increases cancer risk, which can lead to inconclusive results. These limitations may prevent patients and their families from getting accurate results to inform their preventative or therapeutic care.

Previously, published evidence of the value of RNA sequencing has been limited by studies with small sample sizes and enriched cohorts. This study by Ambry is the largest to examine the impact of paired DNA and RNA analysis in hereditary cancer testing.

In this study, tests from 43,524 patients who underwent paired DNA-RNA genetic testing using Ambry’s +RNAinsight from March 2019 through April 2020 were examined to determine if the paired sequencing detected more pathogenic variants than DNA testing alone.

The analysis identified patients who had disease-causing alterations that DNA testing alone would have misinterpreted. Examining the RNA data resolved variant findings in 549 patients (1 in 79 patients) by providing the required functional data for more accurate interpretation of splicing variants. In addition, the analysis showed that 1 of every 950 patients had a pathogenic deep intronic variant that would not have appeared in DNA testing alone.

The results from the study may underestimate the total clinical impact because some of the patients’ families who are now eligible for genetic testing were not tested.

“This is the largest study of its kind to show the importance of RNA testing in predicting cancer risk,” said Carrie Horton, senior clinical research specialist for oncology and first author of the study. “It’s clear that RNA analysis has the potential to become a standard practice for genetic testing to improve hereditary cancer care.”.

Ambry’s +RNAinsight was the first test to provide comprehensive gene coverage for RNA analysis to help classify and detect DNA variants associated with a variety of cancers including breast, ovarian, prostate, colon, pancreatic and uterine. The company says +RNAinsight enables more accurate identification of patients with increased genetic risks for cancer, finds actionable results that may otherwise be missed and, decreases the frequency of inconclusive results.

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