Researchers at the University of Chicago have developed a more sensitive liquid biopsy test that uses RNA instead of DNA to detect cancer. The highlight: using blood samples from patients with colorectal cancer, the test was able to detect the earliest stages of the disease with an accuracy of 95%, significantly improving the non-invasive test methods currently available on the market.

When tumor cells die, they disintegrate and release particles of genetic material into the bloodstream. Standard fluid biopsies rely on this “floating” DNA, known as circulating cell-free DNA (cfDNA), to detect cancer. However, in the early stages of the disease, when the tumor cells are still growing and thriving, there is not much cfDNA in the bloodstream.

“This was a big challenge for early diagnosis. There’s just not enough tumor DNA being released into the blood,” said Dr. Chuan He, John T. Wilson Distinguished Service Professor of Chemistry and Professor of Biochemistry and Molecular Biology at the University of Chicago. “That was a challenge for us and everyone else in the early diagnosis of colorectal cancer, so we decided to look at RNA instead.” Dr. He is the lead author of the new study, which was published this week in Nature Biotechnology.

RNA is a transitional form of the genetic code that copies and executes instructions from DNA to produce proteins that cells need. Analyzing RNA is a good indicator of genetic activity because the presence of RNA means that the cells are active and making proteins.

For the new study, Cheng-Wei Ju, PhD, and Li-Sheng Zhang, PhD, a former postdoctoral fellow in Dr. He’s lab who is now a faculty member at Hong Kong University of Science and Technology, began investigating the possibility of using circulating cell-free RNA (cfRNA) instead of cfDNA for cancer diagnosis and detection.

However, measuring the simple abundance of RNA molecules in the blood is not always reliable, as the amounts can vary greatly depending on the timing and preparation of the samples. Dr. He’s laboratory specializes in studying the biological functions of RNA modifications, i.e. chemical changes to RNA molecules that alter their activity. For the new study, the researchers therefore focused on analyzing the levels of RNA modification in blood samples, which remain relatively stable regardless of how much RNA is present. For example, if an RNA transcript is modified by 30 %, this percentage remains the same regardless of whether it is measured at 100 or 1,000 copies.

Detection of changes in the microbiome

The team worked with samples from colon cancer patients provided by gastroenterologist and longtime collaborator Marc Bissonnette, MD, associate professor of medicine at UChicago. To their surprise, they were not only able to measure changes in cfRNA from human cells, but also detect RNA from gut microbes. Billions of bacteria live with us in the digestive system, and when a cancerous tumor is present, their activity also changes.

Based on previous research on plants, he and his team knew that the level of RNA changes reflects the state of an organism: The more active the organism is, the more changes are made to certain RNAs to maintain that activity. The same pattern was also observed in the colon cancer samples.

“We found that the RNA released by the microbes shows significant differences between cancer patients and healthy people,” says Dr. He. “When a tumor grows in the intestine, the nearby microbiome must be remodeled in response to the inflammation. This affects the neighboring microbes.”

The population of the microbiome also changes much faster than human cells, with more cells dying more frequently and releasing RNA fragments into the bloodstream. This means that a test that measures changes in microbial RNA can detect potential cancer activity much earlier than tests that rely on DNA released by human tumor cells.

Commercial tests that measure DNA or RNA abundance in stool are about 90% accurate in later stages of cancer, but less than 50% accurate in early stages. The new test based on RNA modifications was almost 95% accurate overall and also accurate in the earliest stages of cancer.

“This is the first time that RNA modifications have been used as a potential biomarker for cancer, and it looks like it is much more reliable and sensitive compared to RNA abundance,” Dr. He said. “The fact that we are able to detect the cancer at these early stages is unprecedented.”

Original Paper:

Modifications of microbiome-derived cell-free RNA in plasma discriminates colorectal cancer samples | Nature Biotechnology

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