When a tumor starts to grow in the body, small bits of its genetic material may break away and float off into the bloodstream. This so-called cell free DNA can be used to identify cancer at very early stages. In a breakthrough, scientists have now developed a method for detecting small amounts of cell-free RNA.
When a cell is transcribing active genes, they are copied into RNA sequences. There are cases in which some of this RNA ends up in the bloodstream too. A variety of cells might release these RNA molecules, some of which may be normal while others may come from diseased or dying cells. The majority of these RNA molecules tend to come from cells that generate components of blood, however, and not from tumors. As such, all of that RNA from blood-forming or hematopoietic cells tends to mask the other cell-free RNA molecules in circulation, which are present at much lower levels.
Researchers have now created a technique that can reveal these disease-related RNA molecules, however. This tool, called RARE-seq, can asses blood samples to find cell-free RNA that has come from tumors. This method is about 50 times more sensitive than other sequencing techniques.
In this study, RARE-seq (random priming and affinity capture of cell-free RNA fragments for enrichment analysis by sequencing) was used to analyze 437 plasma samples from 369 volunteers, some of whom had various types of cancer at different stages while others were healthy.
This method was able to reveal signatures of lung cancer at different stages of disease in a group of lung cancer patients. The method also identified some other conditions that are not related to cancer and RNA transcripts that were produced after exposure to vaccines.
While more validation and testing will be needed, this method could offer a new way to diagnose cancer or some other disorders at very early stages, and in a non-invasive way. Diseases that are in progress could also be monitored with this tool.
Molecular probes were used to find 4,737 genes that are expressed at low levels or in rare cases, and 50 genes that are commonly expressed. These rare genes are not usually expressed in a way that results in them ending up in plasma samples from healthy individuals; so the presence of these RNA molecules may point to a disease.
Computational tools were used to filter the gene expression data collected in this work. Then, RARE-seq was able to diagnose cancer in 34% of cases in which ctDNA analysis missed the diagnosis. RARE-seq also found genetic mutations that drive cancer growth in 28% of patients with lung adenocarcinoma and 1% of controls.
The technique could also find evidence of vaccine exposure; it found transcripts associated with mRNA vaccines as many as six weeks afterward the vaccine was administered. It also found transcripts related to lung injury, and COVID-19 infection.
This effort may help future blood tests deliver far more information to patients and clinicians.
Sources: Medical Express, Nesselbush et al Nature 2025, Rounge et al Nature 2025