RNA-Based Liquid Biopsy Detects Early Colon Cancer With 95% Accuracy

A new approach using RNA instead of DNA has improved the accuracy of liquid biopsy tests for early-stage colorectal cancer, according to a study by researchers at the University of Chicago. The method, which measures chemical modifications in RNA fragments from both human and microbial sources, was able to detect early disease with 95% accuracy using blood samples.

Shifting the focus from DNA to RNA

Liquid biopsies are diagnostic tools that detect cancer-associated genetic material in the bloodstream. Most current tests focus on circulating cell-free DNA (cfDNA), which is released by dying tumor cells. However, in early stages of cancer, tumor cells are more likely to be proliferating rather than dying, resulting in lower cfDNA concentrations. This limits the sensitivity of standard cfDNA-based liquid biopsies for early detection.

“That has been a major challenge for early diagnosis. You just don't have enough tumor DNA released into the blood,”

Dr. Chuan He.

To overcome this challenge, researchers focused on circulating cell-free RNA (cfRNA), which reflects ongoing genetic activity. RNA acts as a messenger between DNA and protein synthesis, offering a dynamic view of cellular processes. Yet, measuring RNA abundance alone is often unreliable because RNA levels can fluctuate depending on sample collection conditions.

To address this limitation, the team measured RNA modifications – chemical changes that influence RNA behavior. Unlike total RNA levels, the proportion of modified RNA remains stable across different sample conditions. For instance, if 30% of an RNA transcript is chemically modified, that proportion is consistent regardless of the overall RNA quantity.

Capturing signals from gut microbes

Researchers also found that the cfRNA test captured signals from microbial RNA originating in the gut. These microbes, which coexist with human cells in the digestive system, release RNA fragments into the bloodstream as they die. Since microbial populations change rapidly and respond to inflammatory conditions such as cancer, the analysis of RNA modifications in microbial RNA offers an additional layer of early detection.

“In the gut when you have a tumor growing, the nearby microbiome must be reshaped in response to that inflammation. That affects the nearby microbes.”

Dr. Chuan He.

The study analyzed blood samples from patients with colorectal cancer and compared them with healthy controls. Patterns of RNA modification were distinct in cancer samples, both in human- and microbe-derived RNA. These differences enabled the researchers to distinguish cancerous samples with high sensitivity.

Improved accuracy over existing tests

Current commercial tests based on DNA or RNA abundance, particularly stool-based ones, show reduced accuracy for early-stage disease – typically below 50%. In contrast, the new test, which evaluates RNA modification profiles, maintained nearly 95% accuracy across all cancer stages, including the earliest ones.

This study marks the first time RNA modifications have been evaluated as biomarkers for cancer detection in a liquid biopsy context. It also demonstrates the diagnostic potential of integrating host and microbial genetic activity in a single test.

Reference: Ju CW, Lyu R, Li H, et al. Modifications of microbiome-derived cell-free RNA in plasma discriminates colorectal cancer samples. Nat Biotechnol. 2025. doi: 10.1038/s41587-025-02731-8

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