Universität zu Köln

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., Massie, C. E., Tarpey, P. S., Varela, I., Nik-Zainal, S., Davies, H. R., Shlien, A., Jones, D., Raine, K., Hinton, J., Butler, A. P., Teague, J. W., Baxter, E. J., Score, J., Galli, A., Della Porta, M. G., Travaglino, E., Groves, M., Tauro, S., Munshi, N. C., Anderson, K. C., El-Naggar, A., Fischer, A., Mustonen, V., Warren, A. J., Cross, N. C. P., Green, A. R., Futreal, P. A., Stratton, M. R. and Campbell, P. J. (2011). Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts. N. Engl. J. Med., 365 (15). S. 1384 - 1396. WALTHAM: MASSACHUSETTS MEDICAL SOC. ISSN 1533-4406

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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.)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Papaemmanuil, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cazzola, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boultwood, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Malcovati, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vyas, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bowen, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pellagatti, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wainscoat, J. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hellstrom-Lindberg, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gambacorti-Passerini, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Godfrey, A. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rapado, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cvejic, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rance, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED McGee, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ellis, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mudie, L. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stephens, P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED McLaren, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Massie, C. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tarpey, P. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Varela, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nik-Zainal, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Davies, H. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shlien, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jones, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Raine, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hinton, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Butler, A. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Teague, J. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baxter, E. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Score, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Galli, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Della Porta, M. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Travaglino, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Groves, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tauro, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Munshi, N. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Anderson, K. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED El-Naggar, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mustonen, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Warren, A. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cross, N. C. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Green, A. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Futreal, P. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stratton, M. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Campbell, P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-487305
DOI:	10.1056/NEJMoa1103283
Journal or Publication Title:	N. Engl. J. Med.
Volume:	365
Number:	15
Page Range:	S. 1384 - 1396
Date:	2011
Publisher:	MASSACHUSETTS MEDICAL SOC
Place of Publication:	WALTHAM
ISSN:	1533-4406
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNMT3A MUTATIONS; FREQUENT MUTATION; GENE ASXL1; CLASSIFICATION; MECHANISMS; PATHWAYS; PATTERNS; TET2 Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48730