title: SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts.
abstract: Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom;
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine, University of Pavia, Pavia, Italy;
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ambaglio
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Monika
authors.initials: M
authors.lastname: Jansson
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Gunilla
authors.initials: G
authors.lastname: Walldin
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine, University of Pavia, Pavia, Italy;
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.affiliation: Department of Hematology and.
authors.forename: Klas
authors.initials: K
authors.lastname: Raaschou-Jensen
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Erica
authors.initials: E
authors.lastname: Travaglino
authors.affiliation: Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark;
authors.forename: Klaus
authors.initials: K
authors.lastname: Kallenbach
authors.affiliation: Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden;
authors.forename: Viktor
authors.initials: V
authors.lastname: Ljungström
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Simona
authors.initials: S
authors.lastname: Conte
authors.affiliation: Department of Pathology, and.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boveri
authors.affiliation: Department of Internal Medicine, University of Pavia, Pavia, Italy; Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Rosangela
authors.initials: R
authors.lastname: Invernizzi
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden;
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström Lindberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000756:Anemia, Sideroblastic / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000145:classification* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D055815:Young Adult
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human