April 16, 2018
Blood and marrow transplant, or BMT, is a lifesaving and effective treatment for many patients, but the procedure can cause serious and life-threatening complications. New research out of Roswell Park Comprehensive Cancer Center and The Ohio State University has identified a link between rare variants in a number of novel genes and survival after transplantation of blood and marrow from an unrelated donor, opening avenues for improving individual risk prediction and prognosis for patients undergoing BMT.
A collaborative research team led by Qianqian Zhu, PhD, of Roswell Park and Lara Sucheston-Campbell, PhD, of the Colleges of Pharmacy and Veterinary Medicine at Ohio State and The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute has published new findings in Blood, the journal of the American Society of Hematology, detailing their study of genetic variants across the entire human genome that cause protein changes.
They genotyped the protein-making regions across the entire genome of about 2,500 acute leukemia patients and their human leukocyte antigen (HLA)-matched unrelated blood or marrow donors and found a number of novel genes that significantly impact survival after BMT. The team found that when recipients and donors do not have the same genotype at a variant in a testis expressed gene —TEX38 — the risk of death due to transplant-related causes was much higher. This finding was even more pronounced when either the recipient or donor was female. The team also discovered that patients who had donors with rare variants in another gene, NT5E, had a significantly lower chance of dying from their leukemia following BMT.
This new study is the first to analyze the contribution of rare genetic variants to survival outcomes after BMT from an HLA-matched unrelated donor, and may help optimize donor selection to improve outcomes for patients undergoing transplant. The authors note that the discovered change in the TEX38 antigen makes it bind strongly with certain MHC-class I molecules, which are associated with immune responses and have previously been shown to
be important in BMT outcomes. The analyses also showed that the donor variants in NT5E probably reduce the enzyme activity of the gene — an observation that supports recent preclinical studies showing that targeted blockade of NT5E can slow down tumor growth.
“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after BMT,” says Dr. Zhu, co-first author of the study and Assistant Professor in the Department of Biostatistics and Bioinformatics and Director of the Statistical Genetics & Genomics Resource at Roswell Park. “Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”
Collaborating researchers include Li Yan, PhD, Assistant Professor in the Department of Biostatistics and Bioinformatics at Roswell Park, co-first author of the study, and Theresa Hahn, PhD, Professor of Oncology in the Department of Medicine at Roswell Park, co-last author of the study. This study was performed in collaboration with the Center for International Blood and Marrow Transplant Research (CIBMTR) and Be The Match®.
The study, “Exome Array Analyses Identify New Genes Influencing Survival Outcomes after HLA-Matched Unrelated Donor Blood and Marrow Transplantation,” is available online at bloodjournal.com. This research was supported by grants from two National Institutes of Health agencies: the National Heart, Lung, and Blood Institute (project no. R01HL102278) and the National Cancer Institute (project no. P30CA016056).