Mutations in donors' stem cells may cause problems for cancer patients: study

A study from Washington University School of Medicine in St. Louis suggests that extremely rare, harmful genetic mutations present in healthy donors' stem cells may be passed on to cancer patients receiving stem cell transplants.

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, say heart damage, graft-versus-host disease and possible new leukemias.

The study analyzed bone marrow from 25 adult patients with acute myeloid leukemia (AML) whose samples had been stored in a repository at Washington University. Samples from their healthy matched donors, who were unrelated to the patients, also were sequenced.

The 25 AML patients 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.

The researchers invented a technique called error-corrected sequencing to identify extremely rare DNA mutations that would be missed by conventional genome sequencing, which allows the researchers to find true mutations that are extremely rare: those present in as few as one in 10,000 cells.

The healthy donors ranged in age from 20 to 58, with an average age of 26. The researchers sequenced 80 genes known to be associated with AML, and identified at least one harmful genetic mutation in 11 or 44 percent of the 25 donors. They further showed that 84 percent of all the various mutations identified in the donors' samples were potentially harmful, and that 100 percent 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.

"We didn't expect this many young, healthy donors to have these types of mutations," said senior author Todd E. Druley, an associate professor of pediatrics. "We also didn't expect 100 percent of the harmful mutations to be engrafted into the recipients. That was striking."

Though the study was not large enough to establish a causal link, the researchers found that 75 percent of the patients who received at least one harmful mutation in the 80 genes that persisted over time developed chronic graft-versus-host disease. Among patients who did not receive mutations in the 80 genes, about 50 percent developed the condition. 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.

"We know that cardiac dysfunction is a major complication after a bone marrow transplant, but it's always been attributed to toxicity from radiation or chemotherapy," Druley said. "It's never been linked to mutations in the blood-forming cells. We can't make this claim definitively, but we have data to suggest we should study that in much more detail."

The study was published on Wednesday in the journal Science Translational Medicine.