Blood-Based Epigenetic Signals Enable Osteosarcoma Disease Monitoring

Osteosarcoma is a rare but aggressive pediatric bone cancer where recurrence and metastasis remain difficult to detect early. Imaging-based surveillance can miss small lesions and exposes children to repeated scans, while conventional liquid biopsies often struggle because tumors shed little circulating tumor DNA. Clinicians therefore face limited options for minimally invasive disease monitoring. New findings demonstrate that epigenetic signals in blood-derived DNA may correlate with disease status in osteosarcoma.

University of Chicago Medicine researchers and collaborators identified epigenetic patterns in fragments of circulating DNA that align with disease state in patients with osteosarcoma. The work, published in npj Precision Oncology, points to a potential blood-based approach for disease tracking. The investigators focused on chemical DNA modifications that regulate gene activity rather than mutation detection alone.

The method, called nano-hmC-seal, chemically labels DNA fragments bearing 5-hydroxymethylcytosine (5‑hmC) to enable genome-wide mapping of gene activity from cell-free DNA (cfDNA). By interrogating epigenetic patterns instead of relying solely on circulating tumor DNA (ctDNA), which is often scarce in osteosarcoma, the strategy provides information similar to RNA sequencing while using plasma DNA rather than tissue biopsies. This framework aims to capture disease-associated transcriptional activity through a minimally invasive blood draw.

In patient blood samples, the team confirmed low ctDNA levels yet observed detectable differences in 5‑hmC profiles across disease states. They defined a 136‑gene signature with elevated 5‑hmC in patients compared with healthy individuals, with many genes linked to bone biology and bone turnover. The signal appeared in patients with primary bone tumors and with bone metastases but was largely absent when metastases were confined to the lungs or lymph nodes, likely reflecting lower DNA shedding from small lesions.

The study was relatively small and designed primarily to test feasibility. According to the authors, larger studies are needed to confirm these findings, evaluate whether cfDNA 5‑hmC profiling can complement existing approaches to tumor DNA detection, and determine its potential to guide treatment decisions or identify relapse earlier. 

“Liquid biopsy technologies have transformed cancer care across many cancer types in recent years, but translating these advances to rare cancers like osteosarcoma has remained a significant challenge,” said first author Evan Neczypor, MD, Internal Medicine Resident at UChicago Medicine.

“We were able to find differences in the hydroxymethylcytosine patterns in cfDNA between patients who had different disease state," said Mark Applebaum, MD, Associate Professor of Pediatrics at UChicago Medicine and senior author of the study. "If we can combine this approach with other techniques for analyzing circulating DNA, it could open up new opportunities to monitor patients and better understand how their disease is changing over time,” 

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