Researchers at the University of Chicago have developed a new liquid biopsy that detects early-stage colorectal cancer with high accuracy by analyzing RNA in blood samples. Unlike traditional biopsies, which require tissue removal, liquid biopsies are less invasive and rely on blood draws to identify cancer-related genetic material. However, current methods that detect circulating tumor DNA in the bloodstream have limited effectiveness for early diagnosis because early-stage tumors release little DNA.
Chuan He, John T. Wilson Distinguished Service Professor of Chemistry and professor of biochemistry and molecular biology at UChicago, explained: “That has been a major challenge for early diagnosis. You just don't have enough tumor DNA released into the blood. That was a challenge for us and everyone else to do early diagnosis of colon cancer, so we decided to look at RNA instead.”
The new test uses RNA as an indicator rather than DNA. The research team found that examining modifications on RNA molecules—chemical changes that remain consistent regardless of the amount present—can reliably signal cancer’s presence even when overall RNA levels fluctuate due to sample timing or preparation.
Graduate student Cheng-Wei Ju and Li-Sheng Zhang, now a faculty member at Hong Kong University of Science and Technology, explored whether measuring these stable modification levels on cell-free RNA could be more effective for detecting cancer. The team worked with patient samples provided by Marc Bissonnette, associate professor of medicine at UChicago.
In addition to detecting human-derived cell-free RNA modifications in patients’ bloodstreams, the researchers were able to analyze microbial RNA from gut bacteria. The activity and modification patterns in these microbes changed noticeably in individuals with colorectal cancer compared to healthy people.
He said: “We found that RNA released from microbes has substantial differences between cancer patients versus healthy individuals. 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.”
Because microbial populations turn over faster than human cells—and release their genetic material more frequently—the test can pick up signs of possible cancerous activity earlier than those relying solely on human tumor DNA fragments.
Current commercial tests based on stool samples measure DNA or RNA abundance with about 90% accuracy for later-stage cancers but drop below 50% accuracy for early stages. In contrast, this new method achieved almost 95% accuracy overall—including at initial disease stages.
“This is the first time RNA modifications have been used as a potential biomarker for cancer, and it looks to be much more reliable and sensitive compared to RNA abundance,” He said. “Being able to detect the cancer at those early stages is unprecedented.”
The research was published in Nature Biotechnology under the title “Modifications of microbiome-derived cell-free RNA in plasma discriminates colorectal cancer samples.” It was supported by several organizations including the Ludwig Center for Metastasis at UChicago, Rolfe Foundation, National Institutes of Health, Hong Kong Research Grants Council, Howard Hughes Medical Institute and Institute for Translational Medicine.
Additional authors include Ruitu Lyu, Han Li, Jiangbo Wei, Urszula Dougherty, Akushika Kwesi, Alexander Luna, Xuanhao Zhu, Xiaolong Cui, Bochen Jiang, Yiyi Ji, Peng Xia, Diana C. West-Szymanski, Chenxi Sun, Yuhao Zhong, Chang Ye, Angelica Moran, Christopher Lehmann and Eric Pamer from UChicago; Alberto J. Parra Vitela from Advocate Lutheran General Hospital; Shenghai Shen from Hong Kong University of Science and Technology; Yunzheng Liu from California Institute of Technology; Liangliang Wang from Chinese Academy of Sciences; Yuzhi Xu from New York University; and Wei Zhang from Northwestern University.