Researchers have identified a previously overlooked set of small RNA molecules that can act as a “barcode” for cancer type and may be detectable in blood, raising the prospect of a new kind of liquid biopsy that does not require prior sequencing of a patient’s tumor.
In a study published in Cell Reports Medicine, investigators systematically cataloged so-called “orphan” non-coding RNAs – short RNA fragments found in cancer but not in normal tissues – and termed them oncRNAs. Across 32 tumor types, the team reported more than 260,000 high-confidence oncRNAs, many of which showed highly specific patterns tied to the tissue where the cancer originated.
A key observation was that the simple presence-or-absence pattern of oncRNAs in a sample functioned as a digital signature that could distinguish cancer types and, in some cases, cancer subtypes. Using a machine-learning classifier trained on these binary patterns, the authors demonstrated that oncRNA barcodes could accurately identify tissue of origin in tumor sequencing datasets.
This type of molecular fingerprinting could support clinical questions that remain challenging with current liquid biopsy approaches, particularly in breast cancer minimal residual disease monitoring. The authors noted that circulating tumor DNA assays can be difficult to apply after therapy because tumor DNA levels may be extremely low, sometimes requiring personalized, tumor-informed assay design. In contrast, oncRNAs may offer a tumor-naive strategy because cancer cells appear to actively release some oncRNAs into the cell-free space.
To test whether this signal could inform patient outcomes, the researchers conducted a retrospective analysis using serial serum samples from 192 breast cancer patients treated with neoadjuvant chemotherapy in the I-SPY 2 trial. They measured a “residual oncRNA burden” by comparing total circulating oncRNA levels before treatment and prior to surgery. Changes in this burden were associated with short-term treatment response measures and also predicted long-term survival outcomes.
If validated prospectively, an oncRNA-based assay could expand laboratory options for post-treatment monitoring by providing a blood-accessible biomarker signal that may not depend on tracking tumor mutations – potentially enabling simpler, earlier detection of persistent disease and better risk stratification after therapy.
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