Circulating DNA Size Matters for Liquid Biopsies

July 19, 2016
Circulating DNA Size Matters for Liquid Biopsies
Source: Getty Images

In a new study led by investigators at the University of Utah School of Medicine, researchers report on their recent findings on an advance that could directly increase the sensitivity of liquid biopsies. These new minimally invasive blood tests have been growing in popularity over the past few years on the basis of their potential to reduce, and possibly even eliminate, the need for the sometimes painful and risky procedures involved in sampling tumors, particularly those that reside deep within the body. Yet, thus far, the utility of the test has been limited by its sensitivity, particularly in its detection of solid tumors that have not yet metastasized.  

Liquid biopsies work by detecting pieces of DNA from tumors that are shed into the blood. However, so-called circulating tumor DNA (ctDNA) can be difficult to pick out from the abundant pieces of circulating DNA from healthy cells that are also present—analogous to finding a needle in a haystack. In the new study, the scientists demonstrated that the fragments of ctDNA and healthy DNA in cancer patients are disproportionally sized—a property that can be exploited to distinguish between the two populations of DNA.

"This development has the potential to enable earlier detection of solid tumors through a simple blood draw by substantially improving our ability to detect very low quantities of circulating DNA derived from tumor cells," explained lead study author Hunter Underhill, M.D., Ph.D., assistant professor of pediatrics at the University of the Utah in the Division of Medical Genetics.

The research team initially discovered size difference between ctDNA and healthy circulating DNA in animal tumor models created by inducing tumors with human cancer cells. In a model of glioblastoma, a brain cancer that does not metastasize outside of the brain, they could readily see that the length of ctDNA was smaller than healthy DNA by 20–50 base pairs. However, the researcher wanted to determine if these findings were a species-specific phenomenon, limited to animal tumor models, or if this was a normal biologic occurrence that may also be present in cancer patients.

The findings from this study were published recently in PLOS Genetics in an article entitled “Fragment Length of Circulating Tumor DNA.”

Subsequently, the investigators compared circulating DNA from melanoma patients to that from healthy volunteers. They found that their observations from animal models held true in that the average length of all the DNA pieces present in the blood from melanoma patients was 20–50 base pairs shorter compared to the DNA pieces in blood from healthy volunteers. Upon sequencing the DNA, they found that DNA fragments containing mutated genes—markers of tumors—were typically smaller than healthy versions of the gene from within the same patient.

The results suggested to the research team that ctDNA is more likely to be shorter than circulating healthy DNA. Therefore, they believe that selecting for pieces that are smaller in size should enrich for DNA that comes from tumors. If a person carries them, separation of specific DNA fragments on the basis of size should make them easier to see—akin to reducing the size of the haystack without removing or changing the size of the needle.

The University of Utah scientists tested their supposition by examining DNA from four lung cancer patients, isolating fragments that were 20–50 base pairs shorter than the average total size in circulation. This method increased the proportion of tumor to healthy DNA by 2.5- to 9-fold. The approach was most successful in making a difference in samples from the two patients in which the smaller-sized tumor DNA was not readily apparent, which may represent patients with low tumor burden and previously difficult-to-detect ctDNA.

"It's possible that jump in sensitivity could make the difference between being able to detect cancer, and not," noted Dr. Underhill. "Understanding the mechanism behind this difference may give us new insights into cancer.”

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