@article{10.1172/jci.insight.98962, author = {Meagan A. Jacoby AND Eric J. Duncavage AND Gue Su Chang AND Christopher A. Miller AND Jin Shao AND Kevin Elliott AND Joshua Robinson AND Robert S. Fulton AND Catrina C. Fronick AND Michelle O’Laughlin AND Sharon E. Heath AND Iskra Pusic AND John S. Welch AND Daniel C. Link AND John F. DiPersio AND Peter Westervelt AND Timothy J. Ley AND Timothy A. Graubert AND Matthew J. Walter}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant}, year = {2018}, month = {3}, volume = {3}, url = {https://insight.jci.org/articles/view/98962}, abstract = {Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.}, number = {5}, doi = {10.1172/jci.insight.98962}, url = {https://doi.org/10.1172/jci.insight.98962}, }