Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

E. Papaemmanuil; M. Cazzola; J. Boultwood; L. Malcovati; P. Vyas; D. Bowen; A. Pellagatti; J. S. Wainscoat; E. Hellstrom-Lindberg; C. Gambacorti-Passerini; A. L. Godfrey; I. Rapado; A. Cvejic; R. Rance; C. McGee; P. Ellis; L. J. Mudie; P. J. Stephens; S. McLaren; C. E. Massie; P. S. Tarpey; I. Varela; S. Nik-Zainal; H. R. Davies; A. Shlien; D. Jones; K. Raine; J. Hinton; A. P. Butler; J. W. Teague; E. J. Baxter; J. Score; A. Galli; M. G. Della Porta; E. Travaglino; M. Groves; S. Tauro; N. C. Munshi; K. C. Anderson; A. El-Naggar; A. Fischer; V. Mustonen; A. J. Warren; N. C. P. Cross; A. R. Green; P. A. Futreal; M. R. Stratton; P. J. Campbell; Int Canc Genome Consortium

doi:10.1056/NEJMoa1103283

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

E. Papaemmanuil, M. Cazzola, J. Boultwood, L. Malcovati, P. Vyas, D. Bowen, A. Pellagatti, J. S. Wainscoat, E. Hellstrom-Lindberg, C. Gambacorti-Passerini, A. L. Godfrey, I. Rapado, A. Cvejic, R. Rance, C. McGee, P. Ellis, L. J. Mudie, P. J. Stephens, S. McLaren, C. E. MassieP. S. Tarpey, I. Varela, S. Nik-Zainal, H. R. Davies, A. Shlien, D. Jones, K. Raine, J. Hinton, A. P. Butler, J. W. Teague, E. J. Baxter, J. Score, A. Galli, M. G. Della Porta, E. Travaglino, M. Groves, S. Tauro, N. C. Munshi, K. C. Anderson, A. El-Naggar, A. Fischer, V. Mustonen, A. J. Warren, N. C. P. Cross, A. R. Green, P. A. Futreal, M. R. Stratton, P. J. Campbell, Int Canc Genome Consortium

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.)

Original language	English
Pages (from-to)	1384-1395
Number of pages	12
Journal	New England Journal of Medicine
Volume	365
Issue number	15
DOIs	https://doi.org/10.1056/NEJMoa1103283
Publication status	Published - 2011

Keywords

ACUTE MYELOID-LEUKEMIA
EXPRESSION PROFILES
FREQUENT MUTATION
DNMT3A MUTATIONS
GENE ASXL1
CANCER
GENOME
NEOPLASMS
CELLS
CLASSIFICATION

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1056/NEJMoa1103283

Cite this

Papaemmanuil, E., Cazzola, M., Boultwood, J., Malcovati, L., Vyas, P., Bowen, D., Pellagatti, A., Wainscoat, J. S., Hellstrom-Lindberg, E., Gambacorti-Passerini, C., Godfrey, A. L., Rapado, I., Cvejic, A., Rance, R., McGee, C., Ellis, P., Mudie, L. J., Stephens, P. J., McLaren, S., ... Int Canc Genome Consortium (2011). Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts. New England Journal of Medicine, 365(15), 1384-1395. https://doi.org/10.1056/NEJMoa1103283

@article{57450994fa6448dc8900a62a04f0dc6e,

title = "Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts",

abstract = "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.)",

keywords = "ACUTE MYELOID-LEUKEMIA, EXPRESSION PROFILES, FREQUENT MUTATION, DNMT3A MUTATIONS, GENE ASXL1, CANCER, GENOME, NEOPLASMS, CELLS, CLASSIFICATION",

author = "E. Papaemmanuil and M. Cazzola and J. Boultwood and L. Malcovati and P. Vyas and D. Bowen and A. Pellagatti and Wainscoat, {J. S.} and E. Hellstrom-Lindberg and C. Gambacorti-Passerini and Godfrey, {A. L.} and I. Rapado and A. Cvejic and R. Rance and C. McGee and P. Ellis and Mudie, {L. J.} and Stephens, {P. J.} and S. McLaren and Massie, {C. E.} and Tarpey, {P. S.} and I. Varela and S. Nik-Zainal and Davies, {H. R.} and A. Shlien and D. Jones and K. Raine and J. Hinton and Butler, {A. P.} and Teague, {J. W.} and Baxter, {E. J.} and J. Score and A. Galli and {Della Porta}, {M. G.} and E. Travaglino and M. Groves and S. Tauro and Munshi, {N. C.} and Anderson, {K. C.} and A. El-Naggar and A. Fischer and V. Mustonen and Warren, {A. J.} and Cross, {N. C. P.} and Green, {A. R.} and Futreal, {P. A.} and Stratton, {M. R.} and Campbell, {P. J.} and {Int Canc Genome Consortium}",

year = "2011",

doi = "10.1056/NEJMoa1103283",

language = "English",

volume = "365",

pages = "1384--1395",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "15",

}

Papaemmanuil, E, Cazzola, M, Boultwood, J, Malcovati, L, Vyas, P, Bowen, D, Pellagatti, A, Wainscoat, JS, Hellstrom-Lindberg, E, Gambacorti-Passerini, C, Godfrey, AL, Rapado, I, Cvejic, A, Rance, R, McGee, C, Ellis, P, Mudie, LJ, Stephens, PJ, McLaren, S, Massie, CE, Tarpey, PS, Varela, I, Nik-Zainal, S, Davies, HR, Shlien, A, Jones, D, Raine, K, Hinton, J, Butler, AP, Teague, JW, Baxter, EJ, Score, J, Galli, A, Della Porta, MG, Travaglino, E, Groves, M, Tauro, S, Munshi, NC, Anderson, KC, El-Naggar, A, Fischer, A, Mustonen, V, Warren, AJ, Cross, NCP, Green, AR, Futreal, PA, Stratton, MR, Campbell, PJ & Int Canc Genome Consortium 2011, 'Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts', New England Journal of Medicine, vol. 365, no. 15, pp. 1384-1395. https://doi.org/10.1056/NEJMoa1103283

TY - JOUR

T1 - Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

AU - Papaemmanuil, E.

AU - Cazzola, M.

AU - Boultwood, J.

AU - Malcovati, L.

AU - Vyas, P.

AU - Bowen, D.

AU - Pellagatti, A.

AU - Wainscoat, J. S.

AU - Hellstrom-Lindberg, E.

AU - Gambacorti-Passerini, C.

AU - Godfrey, A. L.

AU - Rapado, I.

AU - Cvejic, A.

AU - Rance, R.

AU - McGee, C.

AU - Ellis, P.

AU - Mudie, L. J.

AU - Stephens, P. J.

AU - McLaren, S.

AU - Massie, C. E.

AU - Tarpey, P. S.

AU - Varela, I.

AU - Nik-Zainal, S.

AU - Davies, H. R.

AU - Shlien, A.

AU - Jones, D.

AU - Raine, K.

AU - Hinton, J.

AU - Butler, A. P.

AU - Teague, J. W.

AU - Baxter, E. J.

AU - Score, J.

AU - Galli, A.

AU - Della Porta, M. G.

AU - Travaglino, E.

AU - Groves, M.

AU - Tauro, S.

AU - Munshi, N. C.

AU - Anderson, K. C.

AU - El-Naggar, A.

AU - Fischer, A.

AU - Mustonen, V.

AU - Warren, A. J.

AU - Cross, N. C. P.

AU - Green, A. R.

AU - Futreal, P. A.

AU - Stratton, M. R.

AU - Campbell, P. J.

AU - Int Canc Genome Consortium

PY - 2011

Y1 - 2011

N2 - 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.)

AB - 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.)

KW - ACUTE MYELOID-LEUKEMIA

KW - EXPRESSION PROFILES

KW - FREQUENT MUTATION

KW - DNMT3A MUTATIONS

KW - GENE ASXL1

KW - CANCER

KW - GENOME

KW - NEOPLASMS

KW - CELLS

KW - CLASSIFICATION

U2 - 10.1056/NEJMoa1103283

DO - 10.1056/NEJMoa1103283

M3 - Article

C2 - 21995386

SN - 0028-4793

VL - 365

SP - 1384

EP - 1395

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 15

ER -

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Abstract

Keywords

UN SDGs

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