cfDNA Methylation Assay Enables Multi-Disease Detection from Single Blood Sample

Many liquid biopsy approaches require deep sequencing to capture low-abundance tumor DNA, complicating broad deployment. Clinicians also need a way to triage positive results to the correct organ system. Researchers now describe a cell-free DNA methylation assay that screens for multiple cancers and organ conditions from a single blood draw.

University of California, Los Angeles (UCLA) investigators developed MethylScan, a method that profiles DNA methylation in cell-free DNA (cfDNA) to detect disease signals system-wide. The approach addresses background cfDNA from blood cells—typically the dominant fraction—by removing much of that noise before sequencing. Enrichment then focuses on methylated DNA fragments originating from solid organs, where pathologic changes can alter methylation patterns. The goal is comprehensive, organ-informed detection from one sample.

Technically, MethylScan uses specialized enzymes to selectively cut unmethylated cfDNA fragments that largely derive from blood cells. A genome-wide hybridization panel then captures the remaining methylated fragments enriched for signals from solid tissues, including diseased organs. By front-end depletion of background, the method reduces sequencing burden while maintaining sensitivity. The team reports that achieving an effective depth of 300× requires about 5 Gb of data per sample, which would cost less than $20 if the price per gigabase is under $4.

In early testing, the study analyzed 1,061 participants spanning liver, lung, ovarian, and stomach cancers; liver diseases such as hepatitis B, hepatitis C, alcohol-related liver disease, and metabolic-associated liver disease; individuals with benign lung nodules; and healthy participants. Machine learning algorithms were applied to the methylation readouts. The assay’s tissue-specific methylation patterns also supported source localization and differentiation among liver disease etiologies, correctly classifying about 85% of patients.

For multi-cancer detection, MethylScan achieved approximately 63% sensitivity across all stages at a specificity of 98%, and about 55% sensitivity in early-stage disease. In liver cancer surveillance among high-risk individuals, including those with cirrhosis or hepatitis B virus (HBV) infection, detection approached 80% at a specificity just over 90%. Performance suggests the workflow can balance accuracy with lower sequencing demands.

Findings were published in Proceedings of the National Academy of Sciences on April 6, 2026. The researchers note that larger prospective trials are needed to validate real-world screening performance. They state the results mark an important step toward a single, affordable blood assay capable of broad disease surveillance.

“Early detection is crucial. Survival rates are far higher when cancers are caught before they spread. If you detect cancer at stage one, outcomes are dramatically better than at stage four,” said Jasmine Zhou, professor of pathology and laboratory medicine and investigator at the UCLA Health Jonsson Comprehensive Cancer Center.

"This study demonstrates that blood-based methylation profiling can deliver clinically meaningful information across multiple diseases," said Zhou. "It's an exciting advancement that brings us closer to realizing the dream of a single assay for universal disease detection."

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