Have you heard someone talk about how much they enjoyed a colonoscopy for colorectal cancer screening? Or what about a heart transplant recipient who finishes an extremely complex surgical procedure only to endure regular cardiac biopsies to monitor the health of a transplanted heart? Both patients and their doctors have long hoped for a reliable alternative that is less invasive, good at detecting disease, and not too expensive.
In a scientific session yesterday, “Emerging Clinical Applications of Circulating DNA Analysis,” Rossa Chiu, PhD, and Michael Oellerich, MD, described a new diagnostic player that may be able to solve the seemingly disparate problems of early cancer screening and monitoring organ transplantation. The hope stems from circulating or cell-free DNA: short pieces of DNA that are freely floating in our blood.
We’re most familiar with cell-free DNA as a tool for detecting fetal chromosome anomalies such as Down syndrome, also known as NIPT/non-invasive prenatal testing. This method has been offered clinically since 2011 and relies on fetal cell-free DNA that is present in maternal blood.
Surprisingly, these same types of cell-free DNA fragments are released during rejection of solid organ transplants and from tumors in patients with cancer. “By analyzing the characteristics of circulating DNA, one may detect pathologies that are associated with cell-free DNA release,” Chiu explained.
Oellerich focused on the role of measuring cell-free DNA to monitor rejection of solid organ transplants. “Organ transplants are also genome transplants,” Oellerich noted, as he emphasized the role of monitoring graft-derived cell free DNA (GcfDNA) in plasma to detect acute organ rejection earlier in the process.
“Organ rejections can be fatal, so you see how important it would be in the future to monitor these patients and you cannot do it by biopsy all the time,” he explained. A new diagnostic option would be to monitor for rejection and infection by sequencing of cell-free DNA in plasma.
Early studies have focused on detecting mutations; however, Chiu emphasized that “diagnostically relevant information may be extracted from multiple facets of the same pool of circulating DNA molecules, including sequence variation, abundance of certain molecules, methylation status, fragment length, and fragment end characteristics.” It will be an amazing advance for laboratories to codify all of this information from a simple peripheral blood specimen.
Widespread adoption of circulating DNA in cancer detection and monitoring graft rejection is not quite around the corner. Chiu stressed that some disadvantages of circulating DNA are “its low abundance, the highly fragmented nature of the cell-free DNA molecules, and interference from cell-free DNA contributed by the turnover of blood cells.” This can be particularly difficult in early cancer detection where very few tumor-derived cell-free DNA molecules are expected to be present in the blood. Several studies have highlighted this challenge by pointing out discordant results between laboratories performing cell-free DNA tests in oncology. However, according to Chiu, “analytical approaches have been developed to overcome these challenges and in some instances, those characteristics have become useful tools.”
Despite the relatively new use of cell-free DNA in clinical diagnostics, they hold much promise in a broad range of applications that include pregnancy, organ transplantation, and cancer. Chiu unequivocally stated that “more circulating tests [will] make their way into routine clinical use. Diverse technologies will be available for circulating DNA analysis [and] mature protocols will be standardized and harmonized.”
Although circulating DNA molecules may be small, their transition from research to clinic cannot be missed.