Whole exome sequencing shows potential to improve efficacy of stem cell transplants
Stem cell transplant donors and recipients are matched using a process known as human leucocyte antigen (HLA) testing, but graft-versus-host disease (GVHD), in which the donor's immune system attacks the recipient’s body, continues to pose a significant threat to transplant patients. Now, researchers at Virginia Commonwealth University (VCU) Massey Cancer Center have sequenced the DNA of a small group of stem cell transplant recipients and their donors and discovered significant variation in their exomes that may help explain why some HLA-matched stem cell transplant recipients still suffer from GVHD.
Recently published in the British Journal of Haematology, the study was led by Amir Toor, M.D., member of the Developmental Therapeutics research program at Massey and associate professor in the Division of Hematology, Oncology and Palliative Care at the VCU School of Medicine. Toor’s team performed whole exome sequencing of DNA samples from nine stem cell transplant recipients and their donors and found that, despite HLA matching, there exists an extensive number of DNA differences that could potentially influence GVHD. The researchers also found greater variation in the DNA, and thus greater potential for GVHD, in unrelated donors compared to related donors. HLA testing identifies the major HLA genes a person has inherited and their corresponding antigens – proteins that help the body's immune system distinguish which cells are "self" and which are "foreign" or "non-self." Exome sequencing analyzes a person’s exome, the portion of their genome – the complete set of genetic information – that contains sequences of DNA that direct the body to make proteins essential for the body to function properly.
“Our study affords new insights into the biological mechanisms impacting stem cell transplantation and raises an important question as to why all patients undergoing stem cell transplantation do not develop graft-versus-host disease,” commented Toor. “Though we only examined a small cohort of patients, our results suggest that whole exome sequencing may help us better understand the factors that influence graft-versus-host disease and could potentially help optimize immunosuppressive therapy following stem cell transplantation in order to improve patient outcomes.”
Moving forward, Toor and his colleagues hope to further utilize whole exome sequencing in a larger sample of patients.
Toor collaborated with Gregory A. Buck, Ph.D., Massey research program member and director of the Center for the Study of Biological Complexity at VCU Life Sciences; Michael C. Neale, Ph.D., professor in the Department of Psychiatry at the VCU School of Medicine; Masoud H. Manjili, D.V.M., Ph.D., member of the Cancer Cell Signaling research program at Massey and associate professor in the Department of Microbiology and Immunology at the VCU School of Medicine; Andrea Ferreira-Gonzalez, Ph.D., chair of the Division of Pathology in the VCU School of Medicine; Max Jameson-Lee, Ph.D., from the Department of Internal Medicine at the VCU School of Medicine; Catherine H. Roberts, Ph.D., from the Bone Marrow Transplant Program at Massey; Vladimir Lee, Ph.D., manager of the Genetic Analysis and Molecular Interactions Core at VCU Life Sciences; Vishal N. Koparde, postdoctoral researcher in the Institute for Structural Biology and Drug Discovery at the VCU School of Medicine; and Myrna G. Serrano, Ph.D., Allison F. Scalora, Ph.D., Nihar U. Sheth, M.S., and Juliana K. Sampson, all from the Center for Biological Complexity at VCU Life Sciences.
This research was supported by Virginia’s Commonwealth Health Research Board, a Massey pilot project grant and, in part, by Massey’s NIH-NCI Cancer Center Support Grant P30 CA016059.