In the last article, we learned that blood can contain ctDNA, small fragments of DNA released from cancer cells. So how do researchers extract and read this DNA?

The process begins with a blood draw. If blood is left too long, its cells break apart and release their own DNA, lowering the already small proportion of ctDNA. Blood is therefore collected in special tubes or processed within a set time. A centrifuge then separates blood cells to obtain the clear plasma, and one milliliter of plasma usually contains only a few to several tens of nanograms of DNA.

This DNA is analyzed using next-generation sequencing (NGS), which reads hundreds of millions of fragments at once and compares them with the reference human genome to find mutations. The technology is already used in patient care. In 2020, the U.S. Food and Drug Administration (FDA) approved the first NGS-based blood test, Guardant360 CDx, to detect EGFR mutations in non-small cell lung cancer, helping doctors choose targeted drugs.

The challenge is that ctDNA is extremely rare. In early-stage cancer, it can make up less than 0.1% of all DNA in the blood, or one cancer fragment among 1,000 normal ones.

Specific gene regions are read thousands of times, but a very small tumor may leave no cancer DNA in the sample at all. In a 2021 study of about 4,000 people, a blood test called Galleri, designed to detect more than 50 cancer types, detected 90.1% of stage IV cancers but only 16.8% of stage I cancers.

Errors are another problem. Mistakes made when DNA is copied and read can occur as frequently as the cancer signals themselves. Researchers therefore attach a unique barcode called a unique molecular identifier (UMI) to each fragment before copying, and treat a mutation as real only if it appears in most copies with the same barcode. Mutations that develop in blood cells with age can also look like cancer signals, so results must be interpreted by experts.

Finding ctDNA means protecting a tiny signal and filtering out noise at every step. As each step becomes more accurate, the chance of finding cancer earlier with a simple blood test will grow.

*This article was written based on what the student learned during her internship.

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