DNA Barcoding Reveals the Complexity of Breast Cancer Liquid Biopsies

Australian scientists have discovered that DNA barcoding can be used to track cancer cells in solid and liquid biopsies, empowering future research into more reliable breast cancer diagnosis and treatment strategies.

Their findings are published in the journal Molecular Systems Biology.

Tumors are composed of different cancer cells that vary in their aggressiveness and sensitivity to treatments, and further research is needed to understand how solid biopsies (from the tumor), or liquid biopsies (from the blood), can capture this diversity.

DNA barcoding technology is a powerful tool to study cancer heterogeneity using lentiviruses to label individual cancer cells with DNA tags. These tags act as barcodes, which can then be tracked and identified in tumor cells and matched biopsies.

Using an optimized DNA barcoding technique, researchers at the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI, and Peter MacCallum Cancer Centre found that tumors in different models shed different amounts of DNA into the bloodstream, even when their cancer cell makeup looks similar.

In a world-first, the team were able to detect the DNA barcodes shed by the primary tumor in blood and plasma samples.

The discovery that DNA tag detectability varies across models, with some showing low recovery even when highly metastatic, indicates that DNA shedding is model-specific and could contribute to false-negative liquid biopsy results.

Antonin Serrano, PhD, who undertook the research at ONJCRI and WEHI and is now a postdoctoral researcher at the University of Melbourne, shares the key findings from this research:

“DNA barcoding enabled us to investigate entire tumors, solid biopsies, and even liquid biopsies. We were then able to accurately quantify how much tumor heterogeneity is captured in biopsies.

“We found that DNA shedding in the bloodstream varied widely, not only depending on necrosis and tumor burden, but also across preclinical models.

“We also found that barcode diversity in the center of primary tumors was significantly higher than in the periphery, which could have significant implications for the interpretation of solid biopsies.”

Professor Delphine Merino, laboratory head at ONJCRI and senior author of the paper, says:

“Our results suggest that both liquid and solid biopsies are, overall, representative of tumor composition, but the results vary between tumors, suggesting that combining both strategies may provide a more accurate representation of the disease.”

Co-senior author and breast cancer clinician professor Sarah-Jane Dawson, Peter MacCallum Cancer Centre, says:

“Liquid biopsies are a noninvasive way to monitor disease progression. This research will help us understand why some tumors are shedding more DNA than others, and could ultimately lead to a better use of liquid biopsies in the clinic.”

In 2026, an estimated 321,910 women and 2,670 men will be diagnosed with invasive breast cancer in the US.

Dr. Tom Weber (WEHI) is a co-first author, and professor Shalin Naik (WEHI) is a co-senior author of the Molecular Systems Biology paper.

This work was supported by Love Your Sister, the National Health and Medical Research Council (NHMRC), and the National Breast Cancer Foundation.