RNA Blood Test Detects Cancers and Resistance to Treatment

This innovative test, created by researchers at Stanford Medicine (Stanford, CA, USA), analyzes RNA molecules found in the bloodstream. Known as cell-free RNA, these molecules are fragments that no longer reside within cells. Blood contains natural byproducts of cell death from various tissues and organs, including cancerous tumors, in the form of both DNA and RNA fragments. After over six years of research, the team developed new techniques to focus on messenger RNA in blood, which they used to identify cancer at different stages, track resistance to treatments, and monitor healthy tissue injury.

Cell-free RNA is present in very small quantities in blood, with around 95% being ribosomal RNA that forms cellular structures responsible for protein synthesis. The new test specifically analyzes messenger RNA, which makes up less than 5% of the total cell-free RNA pool, as these molecules provide a signal about which genes are being expressed as proteins. A paper detailing the methodology and potential uses of this cell-free RNA blood test was published in Nature. The researchers focused their analysis on around 5,000 genes that are typically not found in the blood of healthy individuals, referred to as rare abundance genes. By concentrating on these genes, the test's ability to accurately detect cancer was increased by more than 50 times. The test identified lung cancer RNA in 73% of lung cancer patients, even at early stages. By detecting cell-free messenger RNA, the blood test is able to monitor conditions that don’t rely on the genetic mutations detected by traditional DNA-based tests, such as identifying resistance mechanisms to cancer treatments.

The team also faced a challenge in eliminating the influence of platelets, which contain RNA but no DNA and are responsible for clotting. To address this, the researchers developed a combination of molecular and computational techniques that filter out the effects of platelets, ensuring clearer signals from cancer. This method works not only on fresh blood samples but also on samples that have been stored previously. Beyond cancer detection, the new cell-free RNA method has shown promise in non-cancer applications. It successfully detected elevated levels of normal lung RNA in the blood of patients with acute respiratory distress syndrome (ARDS), a condition that severely damages the lungs and leads to cell death. Additionally, normal lung RNA levels in blood samples from COVID-19 patients correlated with the severity of their illness. The test also found normal lung RNA in the blood of healthy smokers, possibly indicating subtle lung damage caused by smoking.

“Just as archeologists can learn about ancient societies by studying the garbage they left behind, we can learn a lot about what is going on in the cells of a patient’s body based on the degraded RNA molecules that are cleared through the blood,” said co-lead author Maximilian Diehn, MD, PhD, and the Jack, Lulu, and Sam Willson Professor and a Stanford Medicine professor of radiation oncology. “We have developed a sensitive, versatile new type of liquid biopsy that measures cell-free and circulating-tumor RNA and has the potential to enhance personalized medicine in cancer and non-cancer diseases.”

“Unfortunately, a significant fraction of our patients who are being treated for cancer go on to have their therapy stop working, and that resistance is often based on adaptations that do not involve genetic changes, but instead altering how the cells behave or even how the cells look under a microscope,” added Ash Alizadeh, MD, PhD, the Moghadam Family Professor and a professor of medicine, oncology and hematology, who co-led the study with Diehn. “Our non-invasive approach has the potential of avoiding surgical biopsies and identifying these common types of resistance earlier before substantial disease burden shows up on scans or presents with symptoms like pain, providing an earlier opportunity to change treatment and improve outcomes.”