Barcoded DNA Sheds Light on Hidden Complexities in Breast Cancer Detection

Breast cancer comprises diverse tumor cell populations with differing aggressiveness and treatment sensitivity, complicating accurate assessment from a single sample. Solid biopsies preserve tissue architecture but may miss spatial heterogeneity, whereas liquid biopsies provide a noninvasive blood-based snapshot with variable sensitivity. How well each method reflects underlying clonal diversity remains an open diagnostic question. Researchers now report that DNA barcoding can clarify how accurately solid and liquid biopsies capture tumor heterogeneity in breast cancer.

At the Olivia Newton-John Cancer Research Institute (ONJCRI), investigators used an optimized DNA barcoding strategy to label individual cancer cells with lentiviral DNA tags and track them in tumors and matched biopsy samples. The approach enabled detection of barcode-labeled clones in both solid tissue and blood-based specimens. In what the team describes as a world-first, they identified DNA barcodes shed from a primary tumor in blood and plasma.

Tumors across different preclinical models released markedly different amounts of DNA into the bloodstream, even when cellular composition appeared similar. Barcode detectability varied, and some models showed low recovery despite high metastatic potential, suggesting that DNA shedding is tumor-specific and may contribute to false-negative liquid biopsy findings. Barcode diversity was also significantly higher in tumor centers than at the periphery, highlighting sampling limitations of solid biopsies.

Overall, the study found that both liquid and solid biopsies can reflect overall tumor composition, although performance differs between tumors; combining both approaches may provide a more comprehensive disease profile. The work was conducted by ONJCRI in collaboration with WEHI and the Peter MacCallum Cancer Centre and was published in Molecular Systems Biology on February 11, 2026.

“DNA barcoding enabled us to investigate entire tumours, solid biopsies and even liquid biopsies,” said Dr. Antonin Serrano, postdoctoral researcher at the University of Melbourne who undertook the research at ONJCRI and WEHI. “We were then able to accurately quantify how much tumour heterogeneity is captured in biopsies. We found that DNA shedding in the bloodstream varied widely, not only depending on necrosis and tumour burden, but also across preclinical models. We also found that barcode diversity in the centre of primary tumours was significantly higher than in the periphery, which could have significant implications for the interpretation of solid biopsies.”

“Our results suggest that both liquid and solid biopsies are, overall, representative of tumour composition, but the results vary between tumours, suggesting that combining both strategies may provide a more accurate representation of the disease,” said Prof Delphine Merino, Laboratory Head at ONJCRI and senior author of the paper.

Related Links:
Olivia Newton-John Cancer Research Institute
WEHI
Peter MacCallum Cancer Centre