The prognostic impact of somatic point mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
Translational Science Research Grant 2014
Determine the clinical impact of somatic genetic abnormalities in a cohort of 1393 adult and pediatric MOS patients who have undergone allogeneic stem cell transplantation.
Identify mutations in a panel of 120 genes, including 70 genes that are recurrently mutated in myeloid malignancies and 50 genes that are mutated in inherited and acquired bone marrow failure syndromes.
Identify associations between point mutations and post-transplant clinical outcomes, including disease progression or relapse, progression-free survival, non-relapse mortality, and overall survival, as well as other clinicopathologic features.
Develop a comprehensive MOS genetic resource that is available to the Center for International Blood and Marrow Transplant Research (CIBMTR) community. The goal of this project is a definitive and potentially clinical practice-changing analysis of genetic predictors of outcome following allogeneic stem cell transplantation for MOS. Our previous work indicates that specific somatic mutations powerfully predict mortality following HSCT. The proposed study would validate these findings in a definitive cohort, the large repository of samples from the CIBMTR of MOS patients who underwent HSCT. In addition, MOS samples from the CIBMTR would be annotated with mutation status for the full spectrum of point mutations in MOS, enabling current and future investigators to explore the relationship between genetic lesions and clinical phenotype.
R.C. Lindsley, W. Saber, B.G. Mar, R. Redd, T. Wang, M.D. Haagenson, P.V. Grauman, Z.-H. Hu, S.R. Spellman, S.J. Lee, M.R. Verneris, K. Hsu, K. Fleischhauer, C. Cutler, J.H. Antin, D. Neuberg, and B.L. Ebert, Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation, New England Journal of Medicine, 2017, 376, 536. DOI: 10.1056/NEJMoa1611604
Siddhartha Jaiswal, M.D., Ph.D., Pierre Fontanillas, Ph.D., Jason Flannick, Ph.D., Alisa Manning, Ph.D., Peter V. Grauman, B.A., Brenton G. Mar, M.D., Ph.D., R. Coleman Lindsley, M.D., Ph.D., Craig H. Mermel, M.D., Ph.D., Noel Burtt, B.S., Alejandro Chavez, M.D., Ph.D., John M. Higgins, M.D., Vladislav Moltchanov, Ph.D., Frank C. Kuo, M.D., Ph.D., Michael J. Kluk, M.D., Ph.D., Brian Henderson, M.D., Leena Kinnunen M.Sc., Heikki A. Koistinen, M.D., Ph.D., Claes Ladenvall, Ph.D., Gad Getz, Ph.D., Adolfo Correa, M.D., Ph.D., Benjamin F. Banahan, Ph.D., Stacey Gabriel, Ph.D., Sekar Kathiresan, M.D., Heather M. Stringham, Ph.D., Mark I. McCarthy, M.D.,* Michael Boehnke, Ph.D.,* Jaakko Tuomilehto, M.D., Ph.D., Christopher Haiman, Sc.D., Leif Groop, M.D., Ph.D., Gil Atzmon, Ph.D., James G. Wilson, M.D., Donna Neuberg, Sc.D., David Altshuler, M.D., Ph.D.,* and Benjamin L. Ebert, M.D., Ph.D.†, Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes, England Journal of Medicine 2014, 371, 2488. DOI: 10.1056/NEJMoa1408617