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Ambry Genetics Study Finds RNA Testing Can Clarify Role of Variants in Hereditary Cancer Genes

NEW YORK – Adding RNA-based genetic testing to DNA tests can clarify what variants of uncertain significance in hereditary cancer genes mean and change how patients' care is managed, according to a new analysis led by researchers at Ambry Genetics.

While DNA-based genetic testing can identify individuals who have inherited cancer predisposition syndromes, it does not always provide a conclusive result. At the American College of Medical Genetics and Genomics annual meeting this year, Ambry Genetics researchers reported preliminary results indicating that supplementing DNA-based genetic testing with RNA-based testing could improve the classification of variants of uncertain significance. The firm additionally announced earlier this month that it was adding RNA sequencing to its existing DNA sequencing offering, calling the new service +RNAinsight.

As the researchers reported today in JAMA Network Open, the addition of RNA-based genetic testing clarified 88 percent of the inconclusive variants they had found in genes linked to hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer cases and led to changes in clinical management for 44 percent of patients. They further estimated that the addition of RNA-based testing could help 1 in 43 individuals undergoing hereditary cancer predisposition genetic testing.

"Adding RNA genetic testing to standard DNA testing for hereditary cancer risk needs to be the standard of care," Rachid Karam, director of the Translational Genomics Lab at Ambry Genetics and first author of the new study, said in a statement. "Our data shows +RNAinsight will let thousands of more patients know if they have genetic variations that increase their risks for cancer and take action."

For the study, the researchers invited 909 families in which variants thought to affect splicing in a hereditary cancer-linked gene — such as BRCA1, BRCA2, MLH1, and CDH1— had been found to submit samples for additional RNA-based testing. Only about 10 percent of eligible families submitted new samples.

At the time the researchers conducted their analysis, 64 variants from 68 families had undergone variant assessment and reclassification based on the RNA data. Of these, 88 percent were initially classified as variants of uncertain significance and13 percent as likely pathogenic variants.

After adding RNA analysis, 88 percent of the variants of uncertain significance had a change in status, with 47 percent upgraded to likely pathogenic variants and 41 percent downgraded to likely benign variants. Seven could not be reclassified due to insufficient evidence.

Additionally, half of the likely pathogenic variants were upgraded to pathogenic, while two were downgraded to variants of uncertain significance and two remained likely pathogenic. All the likely pathogenic variants upgraded to pathogenic variants affected CDH1, the researchers noted.

For 44 percent of cases, the amended results led to changes in patients' clinical management, according to a survey of the patients' clinicians. Most commonly, this change involved increased surveillance, such as more frequent colonoscopies, or discussion of risk-reducing procedures for individuals whose variants were upgraded, the researchers noted. Downgrading of variants generally did not lead to changes in patient management.

For 78 percent of cases, amended results also led to changes in recommendations for family members, such as recommendations against cascade testing or a decrease in follow-up visits.

Based on the prevalence of likely pathogenic variants or variants of uncertain significance that affect splicing, the researchers estimated that the addition of RNA-based testing would benefit 1 in 43 individuals undergoing hereditary cancer predisposition genetic testing.

The firm plans to offer RNA-based testing at the same time as DNA-based testing to avoid the loss to follow up they observed in the study.