title: Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes.
abstract: Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. thol.felicitas@mh-hannover.de
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Sofia
authors.initials: S
authors.lastname: Kade
authors.forename: Carola
authors.initials: C
authors.lastname: Schlarmann
authors.forename: Patrick
authors.initials: P
authors.lastname: Löffeld
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.forename: Britta
authors.initials: B
authors.lastname: Kölking
authors.forename: Martin
authors.initials: M
authors.lastname: Wichmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Görlich
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011237:Predictive Value of Tests; D011379:Prognosis; D012261:Ribonucleoproteins / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors; D000072668:Splicing Factor U2AF; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C484334:ZRSR2 protein, human; D000090243:Nucleophosmin; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors