title: Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes.
abstract: A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1(mut) patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2(mut) patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2(mut) patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2(mut) patients. U2AF35(mut) patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2(mut)/TET2(wt) (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.
authors.affiliation: Institut Gustave Roussy, 39 rue Camille Desmoulins,Villejuif, France.
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.forename: Véronique
authors.initials: V
authors.lastname: Gelsi-Boyer
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Nadine
authors.initials: N
authors.lastname: Carbuccia
authors.forename: Claire
authors.initials: C
authors.lastname: Hidalgo-Curtis
authors.forename: Véronique
authors.initials: V
authors.lastname: Della Valle
authors.forename: Lucile
authors.initials: L
authors.lastname: Couronné
authors.forename: Laurianne
authors.initials: L
authors.lastname: Scourzic
authors.forename: Virginie
authors.initials: V
authors.lastname: Chesnais
authors.forename: Agnes
authors.initials: A
authors.lastname: Guerci-Bresler
authors.forename: Bohrane
authors.initials: B
authors.lastname: Slama
authors.forename: Odile
authors.initials: O
authors.lastname: Beyne-Rauzy
authors.forename: Aline
authors.initials: A
authors.lastname: Schmidt-Tanguy
authors.forename: Aspasia
authors.initials: A
authors.lastname: Stamatoullas-Bastard
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Thomas
authors.initials: T
authors.lastname: Prébet
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D000072668:Splicing Factor U2AF; D016019:Survival Analysis
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C484334:ZRSR2 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors