Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

By E. Papaemmanuil, M. Cazzola, J. Boultwood, L. Malcovati, P. Vyas, D. Bowen, A. Pellagatti, J. Wainscoat, E. Hellström-Lindberg, C. Gambacorti-Passerini and 38 more. New England Journal of Medicine, 2011

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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.)

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/ffd5cf84156ba951efa1adf9cc1f09c0ec1dd5a3

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Citations in the corpus

Age-related clonal hematopoiesis associated with adverse outcomes. (2014, positive): “This finding is consistent with the results of previous studies that showed that DNMT3A and TET2 mutations were frequent and early events in AML and the myelodysplastic syndrome.(9,10,14,16) Murine models of DNMT3A or TET2 loss of function have shown that mutant hematopoietic stem cells have altered”
Heterogeneity of genomic evolution and mutational profiles in multiple myeloma (2014, positive): “To identify somatically acquired coding point mutations, we used CaVEMan (Cancer Variants through Expectation Maximization) 23,54 , an algorithm that uses a naı¨ve Bayesian classiﬁer to estimate the posterior probability of each possible genotype (wild type, germline SNP, somatic mutation) at a give”
Cancer therapy shapes the fitness landscape of clonal hematopoiesis (2020, neutral): “As the design of our panel limits interrogation to bona fide cancer genes, we annotated each mutation on the basis of its putative role in cancer pathogenesis using OncoKB 25 and recurrence in an in-house dataset of myeloid neoplasms 26–28 (see Methods).”
Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. (2017, background): “Multiple studies have shown that somatic mutations in the SF3B1 gene are associatedwith a good impact on overall survival and disease progression to acute myeloid leukemia in patients with myelodysplastic syndromes.(100,102)”