title: Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.
abstract: In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
authors: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia, Pavia, Italy.
authors: Luca
authors: L
authors: Malcovati
authors: Elli
authors: E
authors: Papaemmanuil
authors: David T
authors: DT
authors: Bowen
authors: Jacqueline
authors: J
authors: Boultwood
authors: Matteo G
authors: MG
authors: Della Porta
authors: Cristiana
authors: C
authors: Pascutto
authors: Erica
authors: E
authors: Travaglino
authors: Michael J
authors: MJ
authors: Groves
authors: Anna L
authors: AL
authors: Godfrey
authors: Ilaria
authors: I
authors: Ambaglio
authors: Anna
authors: A
authors: Gallì
authors: Matteo C
authors: MC
authors: Da Vià
authors: Simona
authors: S
authors: Conte
authors: Sudhir
authors: S
authors: Tauro
authors: Norene
authors: N
authors: Keenan
authors: Ann
authors: A
authors: Hyslop
authors: Jonathan
authors: J
authors: Hinton
authors: Laura J
authors: LJ
authors: Mudie
authors: James S
authors: JS
authors: Wainscoat
authors: P Andrew
authors: PA
authors: Futreal
authors: Michael R
authors: MR
authors: Stratton
authors: Peter J
authors: PJ
authors: Campbell
authors: Eva
authors: E
authors: Hellström-Lindberg
authors: Mario
authors: M
authors: Cazzola
mesh_terms: D000368:Aged; D000483:Alleles; D003062:Codon; D004252:DNA Mutational Analysis; D004900:Erythroblasts / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D012727:Sex Characteristics; D016019:Survival Analysis
chemical_list: D003062:Codon; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human