Ambry Genetics SuperLab. Photo courtesy © 2020 Ambry Genetics
Ambry Genetics SuperLab. Photo courtesy © 2020 Ambry Genetics

A study published in Precision Oncology demonstrates that RNA genetic testing, conducted at the same time as DNA testing, identifies more genetic mutations that increase genetic cancer risk than DNA testing alone.[1]

The results of the study shows the first notable improvement in diagnostic yield for high-risk cancer genes in more than 10 years.

Using +RNAinsight™, Ambry Genetics, a division of Konica Minolta Precision Medicine, is the first laboratory offering concurrent RNA and DNA genetic testing for hereditary cancer risk as a commercially available clinical test.

+RNAinsight, paired with Ambry Genetics’ hereditary cancer DNA tests, uses next-generation sequencing to concurrently analyze a patient’s DNA and RNA. This approach not only improves the sensitivity and clarity of genetic testing, it works in tandem with DNA testing to identify patients with or at-risk for hereditary cancer who might otherwise be missed, decrease variants of unknown significance (VUS) in real-time, and provide more accurate results to inform patient care.[2]

Mutations, Variants or errors
Overall, more than 50 hereditary cancer syndromes have been described. Most of these cancers are caused by harmful mutations, also known as variants or errors, that are inherited in an autosomal dominant fashion in which a single altered copy of a gene inherited from one parent is enough to increase a person’s chance of developing cancer. In addition, a number of tests screen for inherited genetic variants that are not associated with named syndromes but have been found to increase cancer risk. This, for example, includes inherited variants in PALB2, which is associated with increased risks of breast and pancreatic cancers, CHEK2, associated with breast and colorectal cancers, BRIP1, RAD51C and RAD51D, associated with ovarian cancer.[3]

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Overall, these mutations in our DNA increase cancer risk, play a major role in about 5% – 10% of all cancers. Genetic testing identifies these inherited mutations and is a critical tool to prevent hereditary cancers or treat them early.

However, standard DNA testing for hereditary cancer risk excludes portions of DNA, and, as a result, misses some mutations. In addition, DNA testing can produce inconclusive results and fail to determine whether a variant increases cancer risk.

These limitations impact patients and their families because doctors may not have the information needed to recommend appropriate preventive, early-detection, or therapeutic steps. Furthermore, relatives may not be referred for genetic testing and obtain the care they would otherwise have gotten if they had learned they had certain mutations.

RNA genetic testing
Adding RNA genetic testing at the same time as DNA testing helps address these limitations. Specifically, RNA genetic testing is an additional line of evidence that helps determine that an uncertain result from DNA-only testing is either benign or pathogenic.

In addition, RNA generic testing also helps identify mutations that DNA-only testing misses.

In the study published Precision Oncology, the authors describe their scalable and targeted approach to RNA genetic testing that is performed concurrently with DNA genetic testing, demonstrating such an approach that identified more mutations than DNA-only testing.

Working together with 19 other leading clinical institutions across the United States, including Mass General Cancer Center, Huntsman Cancer Institute, and the Perelman School of Medicine at the University of Pennsylvania, researchers at Ambry Genetics looked at 18 tumor suppressor genes where the loss of function is known to be associated with increased cancer. Their work resulted in a prospective study on the first 1,000 patients sent in for hereditary cancer testing using RNA testing coupled with DNA.

The study found that RNA testing identified seven patients with pathogenic mutations that would otherwise have received negative or inconclusive results on DNA testing alone. For six of these seven cases, substantial changes to medical management could be or were recommended based on current guidelines.

Clinical diagnostic labs generally apply a reporting range limit to their DNA genetic testing panels because hereditary mutations, variants or errors outside these ranges have a much lower probability of being pathogenic. However, using +RNAinsight expands the reporting range of DNA-based testing. This, in turn, allows for the identification, providing a clear diagnosis of more patients who may otherwise be missed. Image courtesy: © 2020 Ambry Genetics.

“The study findings demonstrate both the feasibility and clinical utility of adding concurrent RNA genetic testing to determine hereditary cancer risk,” said Tyler Landrith, Ph.D., an Ambry scientist, and study co-author.

“[Our] +RNAinsight provides healthcare providers with more accurate results to inform patient care,” Landrith added.

Relative increase
The prospective analysis showed a 9.1% relative increase in diagnostic yield than DNA testing alone. Adding RNA genetic testing also resulted in a 5.1% relative decrease in the number of patients that otherwise would have received inconclusive results with DNA testing alone and would not have learned whether they had increased cancer risk.

“Paired RNA and DNA genetic testing have given answers to my patients who have struggled for years with inconclusive results that left them feeling helpless,” said Community Health Network Genetic Counselor Rebekah Krukenberg.

“With +RNAinsight, I know that I’m providing my patients with the most accurate and conclusive information about their risks for hereditary cancer,” she explained.

The study also validated the accuracy of +RNAinsight, establishing a large control dataset of healthy patients. This dataset allowed study authors to establish a baseline for benign and disease-causing variants across the genes tested.

Previous studies have demonstrated the benefits of RNA genetic testing. However, testing has been traditionally performed as a follow-up to inconclusive DNA testing. This approach to RNA testing has limitations that Ambry Genetics’ +RNAinsight does not have.

Testing at the same time
A previous study showed that only 10% percent of patients invited to receive RNA testing after having undergone DNA testing actually sent in samples. Moreover, retrospective RNA testing only looks at targeted variants and not a full range of possible mutations. Given these limitations, +RNAinsight is made available to all patients at the same time as DNA testing.[4]

[1] Landrith, T., Li, B., Cass, A.A. et al. Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes. npj Precis. Onc. 4, 4 (2020).
[2] Karam R., Krempelyl K, Richardson ME, McGoIdrickl K, Zimmermann H, Connerl B, Landrithl T, et al., RNA Genetic Testing in Hereditary Cancer Improves Variant Classification and Patient Management. Annual Clinical Genetics Meeting (ACMG) 2019 [Poster]
[3] Cancer Causes and prevention. Genetic Testing for Inherited Cancer Susceptibility Syndromes. What genetic tests are available for cancer risk assessment? National Cancer Institute. Online Last accesses February 24, 2020.
[4] Karam R, Conner B, LaDuca H, McGoldrick K, Krempely K, Richardson ME, Zimmermann H, et al. Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. JAMA Netw Open. 2019;2(10):e1913900. doi:10.1001/jamanetworkopen.2019.13900 [Article]

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