Identifying Smaller ctDNA Fragments Improves Sensitivity of Liquid Biopsy

Liquid biopsy is a new technology that facilitates precision medicine.
Liquid biopsy is a new technology that facilitates precision medicine.

Circulating tumor DNA (ctDNA) has shorter fragment sizes than DNA fragments from healthy cells that have died, and this may increase the clinical utility of liquid biopsies.1

DNA not contained within a membrane (cell-free) enters the circulation at cell death, and blood-based liquid biopsies can detect these DNA fragments. However, both healthy and tumor cells release DNA on death, and distinguishing the DNA fragments from the 2 types of cells has been challenging.

This study demonstrates that the fragments of circulating tumor and healthy cell DNA in cancer patients are different sizes, a property that can be exploited to distinguish between the 2 types.

"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," said Hunter Underhill, MD, PhD, the University of Utah School of Medicine. Underhill initiated this research at the laboratory of Jay Shendure, MD, PhD, a professor in genome sciences at the University of Washington.

Observations that ctDNA were smaller in mouse models of glioblastoma and liver cancer led to this research. The size difference was then confirmed by comparing samples from patients with melanoma to those of healthy people.

Next, the researchers examined DNA from 4 patients with lung cancer and isolated fragments that were 20 to 50 base pairs shorter than average size in circulation. That led to an increase in the proportion of tumor to healthy DNA by 2.5-fold to 9-fold.

"It's possible that jump in sensitivity could make the difference between being able to detect a cancer, and not," said Underhill. Together, the findings support the idea that sorting for smaller DNA fragment size could increase the sensitivity of liquid biopsies for tracking many different types of cancers.

Underhill also points out that the discovery may reveal that there is something fundamentally different about how the body processes tumor DNA in circulation.

"Understanding the mechanism behind this difference may give us new insights into cancer," he said.


1. Underhill HR, Kitzman JO, Hellwig S, et al. Fragment length of circulating tumor DNA. PLOS Genetics. 2016 Jul 18. doi: 10.1371/journal.pgen.1006162. [Epub ahead of print]

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