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Ludwig Johns Hopkins researchers develop new DNA detection method to improve liquid biopsies

May 6, 2021, NEW YORK – A team of researchers at the Ludwig Center at Johns Hopkins has developed a far more sensitive and accurate next-generation gene sequencing technology for the detection of rare fragments of mutated DNA shed by tumors into body fluids.

The detection of such DNA fragments—commonly referred to as “liquid biopsies”—holds the promise of easing the detection of cancers at their earliest stages, when they are most likely to be curable.

In a study led by Ludwig Johns Hopkins researchers Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos and MD-PhD student Joshua Cohen and published May 3 in Nature Biotechnology, the team reported the development and analytical assessment of SaferSeqS (for “Safer Sequencing System”). Their report shows that SaferSeqS is a major improvement over a now widely adopted method developed at Ludwig Johns Hopkins a decade ago named Safe Sequencing System. The new SaferSeqS technology improves the sensitivity of mutant DNA detection and reduces the baseline error rate more than 100-fold in comparison to other methods commonly used for such purposes.

SaferSeqS involves efficiently tagging both strands of each original DNA fragment isolated from an individual’s blood with a unique DNA sequence equivalent to a barcode. Doing this efficiently with the small number of degraded DNA molecules present in blood required the development of new biochemical approaches. The method’s accuracy also stems from its use of duplex sequencing, which relies on the structural redundancy of the double-stranded DNA molecule to distinguish real mutations from errors. If both strands of a DNA molecule have corresponding mutations at the same spot, it is far more likely to be authentic than an artifact introduced during the procedure.

To test the specificity and sensitivity of SaferSeqS in a clinically relevant setting, the researchers compared their analysis of samples to previous results from the CancerSEEK test, a single liquid biopsy for eight common cancer types that was developed at Ludwig Johns Hopkins.

The researchers revisited 74 blood samples from patients with cancer that had false negative results—undetectable mutations—in the 2018 CancerSEEK study, which used SafeSeqS, the original method. SaferSeqS markedly improved sensitivity, finding previously undetectable mutations in 68% of the samples tested.

The researchers also demonstrated that their new method reduces the error rate of existing mutation-detection approaches more than 100-fold.

The next step, they say, is to validate the results and demonstrate the clinical usefulness of the technology in prospective clinical trials. The researchers say SaferSeqS will likely be the underlying platform for future CancerSEEK studies.

The Johns Hopkins press release from which this summary is derived can be found here.


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