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Liquid Biopsy Comparison Highlights Cell-Free RNA, Multiomic Approaches for Detecting Gastrointestinal Cancers

Cell-Free Circulating DNA

NEW YORK – New research suggests that circulating cell-free RNA (cfRNA) in blood plasma may provide a more sensitive window into burgeoning gastrointestinal cancers than cell-free DNA (cfDNA), though multiomic analyses appear more informative than individual data types.

"Overall, we reveal a cell-free multi-molecular landscape that is useful for blood monitoring in personalized cancer treatment," co-senior and co-corresponding authors Zhi John Lu and Qian Lu from Tsinghua University and Pengyuan Wang at Peking University First Hospital, and their colleagues wrote in Cell Reports Medicine on Tuesday.

Using up to 161 blood plasma samples from individuals with colorectal cancer (CRC) or stomach adenocarcinoma, together with samples from cancer-free donor individuals, the team compared cfDNA whole-genome sequencing, cfDNA methylation, total cfRNA, and small cfRNA strategies for detecting cancer cases by liquid biopsy, focusing on insights found with more than a dozen genomic, epigenomic, or transcriptomic features found in circulating cell-free DNA or cell-free RNA.

"[W]e present a systematic evaluation of cell-free multiomics data, including methylated cfDNA immunoprecipitation sequencing (cfMeDIP-seq) and cfDNA whole-genome sequencing (cfWGS) as well as total and small cfRNA sequencing (cfRNA-seq)," the authors explained.

When the team compared cancer detection capabilities in samples assessed using two, three, or four approaches — from total cfRNA in combination with cfDNA methylation to total cfRNA plus cfDNA methylation and cfDNA WGS to total cfRNA plus cfDNA methylation, cfDNA WGS plus small cfRNA profiles — it saw that the multiomic methods were more informative than single-omics strategies.

While the researchers analyzed more than three-dozen genes linked to CRC or gastric cancer in the Catalog of Somatic Mutations in Cancer database, they also flagged 30 genes that were recurrently altered in cfDNA or cfRNA samples from the patients. Together, the results suggested that cfRNA-based variations offered a more sensitive look at the underlying cancers, though the suite of genes with apparent alterations differed between the cfRNA and cfDNA samples.

"[W]e revealed considerable differences between the top genes recognized by cfDNA and the top genes recognized by cfRNA," the authors wrote, noting that such differences "indicate that the genetic insights offered by these two modalities are complementary when evaluated within plasma."

Likewise, the investigators reported that cfRNA offered additional clues to the pathways altered in the gastrointestinal cancer cases compared to their cancer-free counterparts. In the initial sample set and follow-up analyses, for instance, they noted changes to cancer-related immune signatures such as T-cell and cancer-associated fibroblast scores linked to cancer stage, prognostic patterns, and other features.

"Quantitative signatures/scores based on noninvasive biomarkers can help clinicians to tailor therapeutic strategies to individual patients," the authors wrote, adding that "gene signatures and functional pathways inferred from plasma sequencing data can provide targets for investigation of the mechanisms that lead to disparate treatment responses."

Even so, they cautioned that a "more thorough exploration of cfRNAs in various extracellular vehicles and ribonucleoproteins is needed" and noted that the circulatory system "conveys biological signals through vesicular mechanisms and alternative modalities."

"A full understanding of cell-free molecules also requires a multifaceted approach that incorporates various technological modalities and experimental paradigms," the authors explained, "such as chromatin immunoprecipitation sequencing of cell-free nucleosomes carrying active chromatin modifications."