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 journalArticle

    745 Citations (Scopus)

    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 languageEnglish
    Pages (from-to)1384-1395
    Number of pages12
    JournalNew England Journal of Medicine
    Volume365
    Issue number15
    DOIs
    Publication statusPublished - 2011

    Keywords

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

    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