Study Published in Nature Partner Journal Precision Oncology Confirms Clinical Utility of Simultaneous RNA and DNA Genetic Testing

DNA-based multigene panel testing (MGPT) is a commonly used approach for the detection of patients with or at-risk for inherited cancers.  Despite years of advancement in genetic testing, patients may still receive uncertain results or receive a negative result despite having a personal or family history suggestive of hereditary cancer.  RNA genetic testing (RGT) can help minimize some of these challenges. 

RNA: The Basics

The RNA transcript is created by a process called splicing, in which protein-coding sequences, or exons, are removed from stretches of non-coding sequences, called introns, and put back together to form a coherent message for our body to create proteins.  Variation in the DNA can cause errors in the way the RNA transcript is spliced together, which can result in a failure for the protein to be properly expressed. 

Uncertain or negative DNA testing results can be reinterpreted using the splicing information we get from RNA genetic testing. Specifically, the splicing (or mis-splicing) of the RNA transcript can be included as one line of evidence that tips an uncertain result towards a benign (normal) or pathogenic (disease-causing) classification allowing us to provide more accurate, actionable results to a patient.  The mis-splicing of RNA can also suggest the location of a previously undetected pathogenic variant, therefore, RGT enables us to find clinically actionable mutations that could otherwise be missed by DNA-only testing. 

Several studies have demonstrated the benefits of RGT; however, much of this work has focused on sequencing the transcriptome.  The transcriptome refers to the complete suite of RNA expressed in a given tissue or sample.  Other groups have used whole transcriptome testing approaches to successfully increase diagnostic yield, however these techniques work best when using a disease-relevant tissue (e.g. muscle tissue for muscle disorders) given that the gene associated with the disease is more likely to be sufficiently expressed in that tissue.  With that said, it is often difficult to obtain the tissue samples needed, therefore, approaches that can use blood to perform targeted sequencing of a desired set of genes is one way to overcome this roadblock.

New Data Published in NPJ Precision Oncology Supports Paired DNA/RNA Genetic Testing for Hereditary Cancer

In our recent publication in NPJ Precision Oncology, we describe our scalable and targeted approach to RNA genetic testing that is performed in parallel with DNA MGPT. We selected 18 tumor suppressor genes where the loss of function is known to be associated with an increased risk of cancer.  Here are some key takeaways:

  • Our analysis required the generation of a healthy control splicing profile to distinguish abnormal splicing from normal splicing: Variability in RNA splicing, or alternative splicing, is normally observed in healthy individuals.  In order to distinguish abnormal splicing results from normal biological variation, we sequenced RNA from the blood of 345 healthy individuals.  We assessed the most common splicing events for the 18 tumor suppressor genes among the healthy population and measured the expression levels of these common splicing events for each gene. Overall our results supported the use of our healthy control splicing profile as a reference to determine abnormal splicing. 
  • RNA genetic testing was able to verify abnormal splicing from the blood of 25 positive controls: Using the healthy controls as a reference, we were able to verify abnormally spliced transcripts from the blood of 25 patients with known pathogenic splicing variants. Among this group, we observed the expected abnormal splicing event for the corresponding pathogenic variant at an expression level higher than average among the healthy controls.
  • RNA genetic testing identified 7 variants classified as disease-causing that would not have been resolved with DNA-testing alone: We tested the performance of RGT on blood samples from 1,000 patients. Results of testing identified disease-causing variants in genes associated with breast and ovarian cancer (BRCA1, BRCA2, ATM), polyposis (MUTYH), and Lynch syndrome (PMS2). Based on current guidelines, significant changes in medical management are recommended for 6 of the 7 variants identified and may impact not only the positive patients, but also their family members.  Without RNA genetic testing, these patients may not have received these clinically actionable results.


Read the Full Study

As RNA genetic testing is implemented on a more widespread basis, it can provide valuable insight to healthcare providers and patients in the diagnosis and management of inherited cancers.

Learn more about +RNAinsight TM, Ambry’s RNA genetic testing, available to order with hereditary cancer panels.

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The information, including but not limited to, text, graphics, images and other material contained on this blog are for informational purposes only. The purpose of this blog is to promote broad understanding and knowledge of various health topics. It is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this blog. Ambry Genetics Corporation does not recommend or endorse any specific tests, physicians, products, procedures, opinions or other information that may be mentioned on this blog. Reliance on any information appearing on this blog is solely at your own risk.


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