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Young Bone Marrow Donors May Transfer Pathogenic Mutations to Cancer Patients

NEW YORK – A new sequencing study has demonstrated that even young bone marrow donors may have pathogenic mutations that can take hold in those receiving stem cell transplants for acute myeloid leukemia (AML) or other blood cancers.

"Transplant physicians tend to seek younger donors because we assume this will lead to fewer complications," co-author Sima Bhatt, an assistant professor of pediatrics at Washington University School of Medicine, said in a statement. "But we now see evidence that even young and healthy donors can have mutations that will have consequences for our patients."

In a paper published online on Wednesday in Science Translational Medicine, Bhatt and her colleagues used deep, error-corrected sequencing — a method designed to detect mutations at levels as low as one in 10,000 cells — to search for somatic mutations in 80 AML-related genes in multiple bone marrow and blood samples from 25 matched bone marrow donors and recipients.

In the process, the team tracked down somatic mutations in 11 of the donors between the ages of 20 and 58 years. The vast majority of those mutations were predicted to be pathogenic, and all of those risk mutations subsequently turned up in corresponding bone marrow samples from stem cell transplant recipients.

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

Scientists have long appreciated the serious complications that may arise when mutation-containing bone marrow is used in stem cell transplants — from the risk of new blood cancers to graft-versus-host disease. Even rare somatic mutations in donated marrow can replicate and expand quickly in immunosuppressed recipients who are also receiving chemotherapy or radiation therapy, the team explained, though the extent of somatic mutations in bone marrow samples from individuals under 50 has not been well characterized.

"There have been suspicions that genetic errors in donor stem cells may be causing problems in cancer patients," Druley said, "but until now we didn't have a way to identify them because they are so rare."

To delve into the bone marrow mutations passed on during stem cell transplantation, the researchers used error-correction sequencing to assess 125 blood or bone marrow samples, focusing on samples collected 100 days and one year after bone marrow transplantation in 25 individuals treated for AML along with matched frozen samples collected from donors at the time of transplant.

Perhaps most concerning, the team noted that graft-versus-host disease eventually occurred in three quarters of the AML patients who received mutation-containing bone marrow and had those mutations in their own marrow later on. In contrast, graft-versus-host disease turned up in around half of the patients who received seemingly mutation-free bone marrow. 

"This 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," Druley said.

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