Journal
BLOOD
Volume 122, Issue 22, Pages 3616-3627Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-08-518886
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Funding
- Specialized Center of Research grant from the Leukemia Lymphoma Society
- Kay Kendall Leukaemia Fund
- Wellcome Trust [077012/Z/05/Z, WT088340MA]
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Cariplo
- MIUR (PRIN)
- FIRB [RBAP11CZLK]
- Fondazione Berlucchi
- Associazione Italiana per la Ricerca sul Cancro Special Program Molecular Clinical Oncology 5 per mille [1005]
- Medical Research Council through the Molecular Haematology Unit and Disease Team Award
- Leukemia Lymphoma Research (LLR) [12019]
- LLR
- Blood Theme in the National Institute for Health Research Oxford Biomedical Research Centre based at Oxford University Hospitals Trust, Oxford
- Swedish Cancer Society
- Leukemia Lymphoma Society
- Cancer Research United Kingdom
- National Institute for Health Research Cambridge Bioresource
- MRC [MC_UU_12009/11, G1000729, MC_U137961146] Funding Source: UKRI
- Medical Research Council [G1000801c, MC_UU_12009/11, MC_U137961146, G1000729] Funding Source: researchfish
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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 inferences on 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 steadily as numbers of drivermutations 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.
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