Concurrent DNA and RNA Sequencing Improves Accuracy of Hereditary Cancer Testing

This dual approach enhances the discovery of new gene variants and refines our understanding of known variants, leading to better identification of individuals at risk for hereditary cancers and more tailored options for treatment and monitoring.

Scientists at Ambry Genetics (Aliso Viejo, CA, USA) explored the impact of pairing DNA and RNA testing on detecting disease-causing germline genetic variants and resolution of variants of uncertain significance (VUS). Their study included 43,524 people who were tested for hereditary cancer risk. They found that using RNA sequencing alongside DNA testing not only improved the rate at which they identified disease-related genetic variants but also reduced the number of inconclusive findings. Specifically, RNA sequencing influenced the classification of 17.1% of splicing variants deemed pathogenic, which is about 1.9% of all variants identified as pathogenic. It also helped to reclassify 71.1% of splicing variants previously labeled as uncertain — equating to 2.1% of all variants of uncertain significance — as benign.

These results are transformative in the field of genetic testing for cancer risk, with a shift towards a more integrated multiomic approach. The advantage of this method is that it gives patients and healthcare providers a more comprehensive and definitive genetic profile for making informed and timely medical decisions. As genetic testing evolves, the integration of RNA sequencing is becoming increasingly important in the pursuit of personalized medicine, significantly improving the ability to detect and categorize genetic variations linked to hereditary cancer.

"The integration of DNA with RNA sequencing into germline cancer predisposition evaluation is the new gold standard for genetic testing,” said Rachid Karam, M.D., Ph.D., VP of Research & Development at Ambry Genetics and lead investigator of the study. “We’ve witnessed a remarkable improvement in diagnostic accuracy and a substantial reduction in inconclusive results. Patients benefit from having access to the most comprehensive genetic testing possible, as demonstrated by the thousands of individuals impacted by RNA testing in our laboratory cohort alone.”

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