A new study from Washington University School of Medicine suggests that extremely rare, harmful genetic mutations present in healthy donors’ stem cells may be passed on to cancer patients receiving stem cell transplants, potentially creating health problems for the recipients. Among the concerns are heart damage, graft-versus-host disease and possible cancer.
A bone marrow transplant is a common treatment for blood cancers, such as acute myeloid leukemia (AML). Such treatment can cure blood cancers but also can lead to life-threatening complications, including heart problems and graft-versus-host disease, in which new immune cells from the donor attack a patient’s healthy tissues.
The intense chemo- and radiation therapy prior to transplant and the immunosuppression given after allow cells with these rare mutations the opportunity to quickly replicate, potentially creating health problems for the patients who receive them, suggests the research, published the journal Science Translational Medicine.
The study, involving samples from patients with AML and their stem cell donors, suggests such rare, harmful mutations are present in surprisingly young donors and can cause problems for recipients even if the mutations are so rare as to be undetectable in the donor by typical genome sequencing techniques. The research opens the door to a larger study that will investigate these rare mutations in many more healthy donors, potentially leading to ways to prevent or mitigate the health effects of such genetic errors in patients receiving stem cell transplants.
“There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients, but until now we didn’t have a way to identify them because they are so rare,” said senior author Todd E. Druley, MD, PhD, an associate professor of pediatrics. The study raises concerns that even young, healthy donors’ blood stem cells may have harmful mutations and provides strong evidence that we need to explore the potential effects of these mutations further.
The authors analyzed bone marrow samples from 25 adult patients with AML. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced. The AML patients were chosen because they each had had samples banked at four separate times: before the transplant, at 30 days post-transplant, at 100 days post-transplant, and one year post-transplant.
Professor Todd Druley, the lead author previously developed a new technique called error-corrected sequencing, to identify extremely rare DNA mutations that would be missed by conventional genome sequencing. Typical next-generation sequencing techniques can correctly identify a mutation that is present in one in 100 cells. The new method, which can distinguish between true mutations and mistakes introduced by the sequencing machine, allows the researchers to find true mutations that are extremely rare down to one in 10,000 cells.
The researchers sequenced 80 genes known to be associated with AML, and they identified at least one harmful genetic mutation in 11 of the 25 donors, or 44%. They further showed that 84% of all the various mutations identified in the donors’ samples were potentially harmful, and that 100% of the harmful mutations present in the donors later were found in the recipients. These harmful mutations also persisted over time, and many increased in frequency. Such data suggest the harmful mutations from the donor confer a survival advantage to the cells that harbor them.
According to the researchers, the study raises questions about the origins of some of the well-known side effects of stem cell transplantation. In general, about half of all patients who receive a stem cell transplant go on to develop some form of graft-versus-host disease. The most common mutation seen in the donors and the cancer patients studied is in a gene associated with heart disease. Healthy people with mutations in this gene are at higher risk of heart attack due to plaque buildup in the arteries.
Wing Hing Wong, Sima Bhatt, Kathryn Trinkaus, Iskra Pusic, Kevin Elliott, Nitin Mahajan, Fei Wan, Galen E. Switzer, Dennis L. Confer, John DiPersio, Michael A. Pulsipher, Nirali N. Shah, Jennifer Sees, Amelia Bystry, Jamie R. Blundell, Bronwen E. Shaw, Todd E. Druley. Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Science Translational Medicine, 2020; 12 (526): eaax6249 DOI:Go To Science Translational Medicine