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When it comes to liquid biopsies, size (of DNA) matters

The presence of epithelial cells in the bloodstream of a woman with metastatic breast cancer was discovered by T.R. Ashworth more than 150 years ago. His discovery would make it possible to determine, decades later, the existence of circulating tumor cells to monitor the evolution and progression of cancer.

The technology known as liquid biopsy has generated new hope in the fight against malignant tumors. Thanks to this technique, as pointed out by Dr. Josep Baselga in an article published in the New York Times, we will be able to determine the response to therapies, and even the appearance of resistances. With the advancements made –Spain is a forerunner in the application of the liquid biopsy to colorectal cancer– it is possible to capture the heterogeneity of a tumor through a single analysis and monitor the genetic changes in real time.

Nonetheless, there are still difficulties involved in using the liquid biopsy on a routine basis in clinical practice. One of the main challenges is the improvement of the sensitivity of the technique, with the aim of discerning between the DNA fragments of circulating tumor cells and those of completely healthy cells. This challenge is even greater in the case of solid tumors that have not metastatized. 

liquid biopsy 1

Source: University of Utah

A study conducted at the University of Utah, published in PLOS Genetics, demonstrated that DNA fragments of the circulating tumor cells have slightly different sizes than those of healthy cells. The size of the sequences can be key to improve the sensitivity of a technique with vast future possibilities. 

“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”, says  Hunter Underhill, one of the study authors. The differences in the size of DNA fragments were initially discovered in animal models of glioblastoma, a type of brain tumor that does not produce metastasis. They were able to see that the DNA of circulating tumor cells was between 25 and 30 base pairs smaller than the DNA of healthy cells. Later, scientists made similar findings in animal models of liver cancer, although it was unknown whether it was a characteristic of the models used or, to the contrary, a biological phenomenon also present in the patients. 

liquid biopsy 2

Source: University of Utah

When they compared the DNA of circulating tumor cells from melanoma patients with that of healthy volunteers, the researchers again observed a difference of size ranging from 20 to 50 base pairs. After sequencing the genetic fragments, they described “a strong evidence that a more general process that shortens ctDNA fragment length relative to normal cell-free DNA from healthy cells is present and is independent of copy number alterations”. Although the etiology of the shorter fragment length associated with ctDNA remains unclear, according to the conclusions published in PLOS Genetics, selecting smaller genetic fragments should enrich the samples in genetic material originating form the tumor, with the aim of improving the sensitivity of the liquid biopsy.

To test their hypothesis, the Utah researchers examined DNA from four lung cancer patients' samples, isolating the genetic fragments that were between 20 and 50 base pairs shorter than the total size of the circulating DNA. They corroborated that, using this simple process, the proportion of DNA from circulating tumor cells was between 2.5 and 9 times greater than that of DNA from benign cells. “It's possible that this jump in sensitivity could make the difference between being able to detect a cancer, and not,” says Underhill. Despite the small sample size, their conclusions support the hypothesis that classifying the shorter DNA fragments could improve the effectiveness and sensitivity of the liquid biopsy. The liquid biopsy is a technology that, as shown by the launch of the start-up GRAIL, promoted by Illumina with the support of Jeff Bezos and Bill Gates, has opened new possibilities in the fight against cancer.