Clinical and biological implications of driver mutations in myelodysplastic syndromes

Elli Papaemmanuil, Moritz Gerstung, Luca Malcovati, Sudhir Tauro, Gunes Gundem, Peter Van Loo, Chris J. Yoon, Peter Ellis, David C. Wedge, Andrea Pellagatti, Adam Shlien, Michael John Groves, Simon A. Forbes, Keiran Raine, Jon Hinton, Laura J. Mudie, Stuart McLaren, Claire Hardy, Calli Latimer, Matteo G. Della PortaSarah O'Meara, Ilaria Ambaglio, Anna Galli, Adam P. Butler, Gunilla Walldin, Jon W. Teague, Lynn Quek, Alex Sternberg, Carlo Gambacorti-Passerini, Nicholas C P Cross, Anthony R. Green, Jacqueline Boultwood, Paresh Vyas, Eva Hellstrom-Lindberg, David Bowen, Mario Cazzola, Michael R. Stratton, Peter J. Campbell

Research output: Contribution to journalArticlepeer-review


Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferenceson subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadilyas numbersof driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.

Original languageEnglish
Pages (from-to)3616-3627
Number of pages12
Issue number22
Publication statusPublished - Nov 21 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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