Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts
Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by ring sideroblasts. Patients with mutations had improved survival as compared with those without mutations. The myelodysplastic syndromes are a...
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| Published in | The New England journal of medicine Vol. 365; no. 15; pp. 1384 - 1395 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Waltham, MA
Massachusetts Medical Society
13.10.2011
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by ring sideroblasts. Patients with mutations had improved survival as compared with those without mutations.
The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia.
1
These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone marrow–biopsy specimens from patients with myelodysplastic syndromes show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of one or more lineages. Target genes of recurrent chromosomal aberrations have been mapped,
2
,
3
and several genes have been identified as recurrently mutated in these disorders, including
NRAS
(encoding neuroblastoma RAS viral oncogene homologue),
TP53
(encoding . . . |
|---|---|
| AbstractList | BACKGROUNDMyelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODSWe used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTSWe identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONSMutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.). Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by ring sideroblasts. Patients with mutations had improved survival as compared with those without mutations. The myelodysplastic syndromes are a heterogeneous group of hematologic cancers characterized by low blood counts, most commonly anemia, and a risk of progression to acute myeloid leukemia. 1 These disorders have increased in prevalence and are expected to continue to do so. Blood films and bone marrow–biopsy specimens from patients with myelodysplastic syndromes show dysplastic changes in myeloid cells, with abnormal proliferation and differentiation of one or more lineages. Target genes of recurrent chromosomal aberrations have been mapped, 2 , 3 and several genes have been identified as recurrently mutated in these disorders, including NRAS (encoding neuroblastoma RAS viral oncogene homologue), TP53 (encoding . . . Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.). |
| Author | Raine, K McLaren, S Teague, J.W El-Naggar, A Pellagatti, A Hellstrom-Lindberg, E Cazzola, M Tarpey, P.S Tauro, S Travaglino, E Score, J Groves, M Varela, I Wainscoat, J.S Cross, N.C.P Della Porta, M.G Papaemmanuil, E McGee, C Ellis, P Hinton, J Fischer, A Campbell, P.J Baxter, E.J Green, A.R Rapado, I Cvejic, A Nik-Zainal, S Galli, A Warren, A.J Shlien, A Mudie, L.J Stephens, P.J Bowen, D Rance, R Malcovati, L Massie, C.E Anderson, K.C Davies, H.R Butler, A.P Munshi, N.C Vyas, P Jones, D Mustonen, V Stratton, M.R Godfrey, A.L Boultwood, J Gambacorti-Passerini, C Futreal, P.A |
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| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24615731$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/21995386$$D View this record in MEDLINE/PubMed http://kipublications.ki.se/Default.aspx?queryparsed=id:123398500$$DView record from Swedish Publication Index |
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| Snippet | Abnormalities in a gene encoding a messenger RNA splicing enzyme were found in nearly two thirds of patients with myelodysplastic syndromes characterized by... Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new... BackgroundMyelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate... BACKGROUNDMyelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate... |
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| SubjectTerms | Biological and medical sciences Bone marrow Deoxyribonucleic acid DNA Erythrocytes - pathology Exons Gene Expression Profiling General aspects Genetic testing Genomes Hematologic and hematopoietic diseases High-Throughput Nucleotide Sequencing Humans Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Medicin och hälsovetenskap Mitochondria mRNA Mutation Myelodysplastic syndrome Myelodysplastic syndromes Myelodysplastic Syndromes - genetics Pathogenesis Phenotype Phosphoproteins - genetics Point Mutation Ribonucleoprotein, U2 Small Nuclear - genetics RNA Splicing Factors Sideroblasts Splicing factors Statistical analysis |
| Title | Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts |
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