SomaticSF3B1Mutation in Myelodysplasia with Ring Sideroblasts

作者：Elli Papaemmanuil, Mario Cazzola, Jacqueline Boultwood, Luca Malcovati, Paresh Vyas, David Bowen, Andrea Pellagatti, James S. Wainscoat, Eva Hellström‐Lindberg, Carlo B Gambacorti-Passerini, Anna L. Godfrey, Inmaculada Rapado, Ana Cvejic, Richard Rance, Chris McGee, Peter Ellis, Laura J. Mudie, Philip J. Stephens, Stuart McLaren, Charles E. Massie, Patrick S. Tarpey, Ignacio Pujol Varela, Serena Nik‐Zainal, Helen Ruth Davies, Adam Shlien, David Jones, Keiran M. Raine, Jonathan Hinton, Adam P. Butler, Jon W. Teague, E. Joanna Baxter, J Score, Anna Gallì, Matteo Giovanni Della Porta, Erica Travaglino, Michael J. Groves, Sudhir Tauro, Nikhil C. Munshi, Kristina Anderson, Adel K. El‐Naggar, Andrej Fischer, Ville Mustonen, Alan John Warren, Nicholas C.P. Cross, Anthony Richard Green, P. Andrew Futreal, Michael R. Stratton, Peter J. Campbell · 发表于：New England Journal of Medicine · 年份：2011 · DOI：10.1056/nejmoa1103283 · 被引用次数：1230 · 研究领域：Acute Myeloid Leukemia Research、Genomics and Rare Diseases、Blood disorders and treatments

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...