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Advanced genetic testing looks for specific inherited changes, known as variants, in a person’s genes. These variants, if harmful, may drive the development of a specific cancer. But the results of genetic testing may also point to variants without a specific effects on the risk of a person developing cancer.

The information about genomic mutations is unique to a specific, individual cancer and may help clinicians identify treatment options designed to target those mutations. Variants known to be harmful, are associated with an increased risk of developing cancer. These variants contribute to about 5 to 10% of all cancers. [1]

Beyond DNA
Genetic testing involves DNA (deoxyribonucleic acid). DNA is broken down into small pieces which are tightly wound into coils, called chromosomes. Humans have 23 pairs of chromosomes, which, in turn, can be further broken down into even smaller pieces of code called genes. Humans have 23 pairs of chromosomes which consist of about 70,000 genes, each with their own function.

In simple terms… DNA stores the genetic information, whereas RNA uses the information to help the cell produces a specific protein…

Ribonucleic acid (RNA), while similar to DNA since both are nucleic acids of nitrogen-containing bases joined by sugar-phosphate backbone, differ functionally and structurally, distinguishing RNA from DNA. Structurally, RNA is a single-stranded where as DNA is double stranded. Furthermore, DNA includes thymine, also known as 5-methyluracil, a pyrimidine nucleobase, while RNA includes uracil, a different pyrimidine nucleobase.

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RNA nucleotides include sugar ribose, rather than the deoxyribose that is part of DNA. Functionally, DNA replicates, maintains and stores the protein-encoding information, representing a ‘blueprint’ for all genetic data, whereas RNA converts this information to enable the cell to synthesize or manufacture, a particular protein.

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Today, the majority, if not all, clinical genetic testing are performed on DNA.

However, research has shown that supplemental RNA testing helps overcome limitations of DNA testing. Performed in tandem, DNA and RNA testing can provide significantly more nuance and accuracy, particularly when it comes to currently ambiguous test results.[2]

Paired DNA + RNA
Launched today, +RNAinsight™, developed by Aliso-Viejo, CA-based Ambry Genetics®, a part of Konica Minolta Precision Medicine, represents a major advancement in genetic testing.

The new test, for the first time ever, enables clinicians to conduct both DNA and RNA genetic testing at the same time. This paired testing identifies, more often than DNA testing alone, whether someone has a genetic mutation that either increases their risk for developing cancer or that may have contributed to their existing cancer.[2][3]

Ambry’s test is the first genetic testing advancement in over a decade to significantly increase the opportunity for clinicians to identify the number of patients with a specific hereditary risk for cancer, referred to as diagnostic yield, in genes including, for example BRCA1 and BRCA2, which may determine the risk for inherited breast and ovarian cancer.

Today, Ambry is also the first and only lab to offer paired RNA and DNA genetic testing for hereditary cancer.

Ambiguous results
As mentioned before, DNA testing alone can produce inconclusive, ambiguous testing results. These results don’t help clinicians in understanding if an error in a person’s DNA, known as genetic variant increases the risk for cancer. Hence, these results are ‘uncertain’ because they cannot be clearly interpreted.

In addition, standard DNA testing for hereditary cancer excludes large portions of DNA, and, as a result, misses variants that cause increased risks for cancer.

Adding RNA to DNA testing helps overcome these limitations for a significant number of people because RNA provides considerably more evidence (or data) than DNA alone, and helps clinicians discern whether the genes in our DNA have variants that may cause an increased risks for cancer.

Aaron Elliott, Ph.D, and Chief Executive Officer of Ambry Genetics. Since joining Ambry in 2008, Elliott has been involved in launching some of the most groundbreaking genetic tests in the industry. In addition to launching the first commercial next generation sequencing gene panel and the first CLIA approved diagnostic exome test, Elliott was involved in a highly-publicized, pivotal Supreme Court decision involving gene patents, in which the United States Supreme Court unanimously ruled that Myriad Genetics’ patents on the BRCA1 and BRCA2 genes were invalid. The ruling ended Myriad’s lucrative monopoly on testing for mutations in the two genes linked to an increased risk of breast and ovarian cancer, ruling that human genes were not eligible for patents because they were products of nature.

Based on the added information, clinicians can help patients and their relatives to try to prevent cancer from developing or to detect cancer at an earlier stage, creating better treatment options and a survival benefit.

“We’ve developed paired RNA and DNA testing to provide more accurate and conclusive results that patients and doctors can act on,” noted Aaron Elliott, Ph.D, and Chief Executive Officer of Ambry Genetics.

“With +RNAinsight, we not only identify mutations that DNA testing alone would miss, we also provide answers for patients who have been dealing with inconclusive results for years,” Elliot added.

This year, almost 700,000 people in the United States are expected to turn to clinical labs for clinical-grade genetic testing to learn whether they have genetic mutations linked with increased risks of cancer. Based on the available data, pairing RNA and DNA testing may help more than 16,000 individuals get the genetic information they need that they might not get from DNA testing alone.

While it is estimated that Ambry’s +RNAinsight will directly help more than 16,000 individuals, the actual number may be much higher. For example, family members can now be tested to learn of their own increased risks. In addition, patients who have previously been tested and who have received inconclusive test results based on DNA testing alone, may now be ‘reclassified’ based on novel paired testing.

Huma Q. Rana, MD, Clinical Director of the Center for Cancer Genetics and Prevention, at Dana-Farber Cancer Institute. Rana provides longitudinal medical management of patients with hereditary cancer predispositions, and also leads multiple research projects studying various hereditary cancer syndromes.

“Paired RNA and DNA genetic testing is a remarkable leap forward. My patients are finally getting answers I was unable to provide before,” said Huma Q. Rana, MD, Clinical Director of Cancer Genetics and Prevention at Dana Farber Cancer Institute.

“In our short time using this technology, we have made meaningful changes to patient care,” she added.

Patient perspective
“Paired RNA and DNA testing has meant everything to me and my family in our fight against cancer, finally letting my brother, sister, and me know we have a genetic mutation that causes Lynch syndrome, which puts us at an increased risk for colorectal and uterine cancers,” explained Turkeesa Looper.

“Past DNA tests never told us that, and now our family, including my nieces and nephews, can also take action,” Looper noted, who, together with two of her siblings, are patients at Indiana Community health and have been working with genetic counselors for the last few years to identify the mutation causing their hereditary cancer.

Pilot study
A prospective analysis of the first 2,500 patients tested with paired RNA and DNA hereditary cancer testing for up to 18 genes, sent in from pilot clinical sites, resulted in a relative increase in diagnostic yield of approximately seven percent.

The impact on diagnostic yield varies by gene, with some genes having a relative diagnostic yield increase of over 15%. BRCA1, PMS2, MSH2, and ATM are among the genes for which we are seeing a greater impact. Hence, paired testing will inform more patients with mutations in high-risk cancer genes know this when DNA testing alone would not have done so. Based on the results, these patients can now benefit from preventive steps, early detection, reduced cancer incidence, and increased survival. It will also directly benefit their relatives who get tested.

Additionally, the data illustrates +RNAinsight’s ability to clarify results that were previously deemed inconclusive as a result of DNA testing alone.

For an example, Ambry’s new test can improve variant detection and classification for patients receiving hereditary cancer testing. In some cases, these patients may receive a so called ‘Variants of Unknown Significance,’ or ‘VUS’ result. This may cause uncertainty and confusion for both the ordering clinician and patient because a VUS result does not provide actionable information to inform medical management since it doesn’t clarify if the patient is at an increased risk for cancer.[2][3]

In contrast, Ambry’s +RNAinsight offers additional evidence that help a clinician understand if the results ar pathogenic or benign. This additional evidence can turn a ‘VUS’ result into an actionable resultspositive or clear, negative result.[2][3]

Ambry’s novel test, which builds on the company’s earlier breakthrough in RNA genetic testing, was able to decrease the number of inconclusive results across the included cancer risk genes by approximately five percent relative to DNA testing alone.

Retrospective testing
For some time Ambry has offered RNA testing retrospectively – looking at RNA after DNA testing was complete. However, while helpful, retrospective RNA testing has a number of limitations that +RNAinsight does not. Such limitations include not being able to identify mutations that the earlier DNA testing failed to find and patients who are lost to follow-up.

Psychological benefits and risks
Because the far reaching consequences, genetic testing poses psychological benefits and risks. For example, a negative result can bring a sense of relief, while, at the same time reducing worry and anxiety. Such a result may also eliminate the need for more frequent checkups and tests that are routine in individuals with a high risk of cancer.

In contrast, a positive test may require additional tests and treatment, and while However, a positive gene mutation does not necessarily mean that an individual will actually develop cancer, it may increase a patient’s anxiety. Some people with positive results will never get cancer.

To make sure that the information makes sense, cancer genetic counseling by a health care professional with expertise in medical genetics and counseling, may help evaluate an individual’s personal and family cancer histories, assess the inherited cancer risk, explain the concepts of genetics and hereditary cancer risks and offer support to individuals and families at risk for cancer.

Given the psychological effect, a genetic counselor may empower individuals to make informed choices and address questions and concerns.

[1] Genetic Testing for Inherited Cancer Susceptibility Syndromes. National Cancer Institute. Online. Last accesses October 2, 2019
[2] Karam R, Krempely K, Richardson M, McGoldrick K, Conner B, Landrith T, Allen K, Yussuf A, Rana H, et al. RNA Genetic Testing in Hereditary Cancer Improves Variant Classification and Patient Management. Poster presentation, Abstract #10318; 2019 Annual Clinical Genetics Meeting organized by The American College of Medical Genetics and Genomics (ACMG)
[3]. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. [Pubmed][Article]

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