title: Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes.
abstract: OBJECTIVE
  To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS).
  
  
  METHODS
  Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct sequencing and for expression levels of ASXL1. The prognostic impact of ASXL1 mutation and expression levels was evaluated in the context of other clinical and molecular prognostic markers.
  
  
  RESULTS
  Mutations in ASXL1 occurred with a frequency of 20.7% in MDS (n = 40 of 193) with 70% (n = 28) of mutations being frameshift mutations and 30% (n = 12) being heterozygous point mutations leading to translational changes. ASXL1 mutations were correlated with an intermediate-risk karyotype (P = .002) but not with other clinical parameters. The presence of ASXL1 mutations was associated with a shorter overall survival for frameshift and point mutations combined (hazard ratio [HR], 1.744; 95% CI, 1.08 to 2.82; P = .024) and for frameshift mutations only (HR, 2.06; 95% CI, 1.21 to 3.50; P = .008). ASXL1 frameshift mutations were associated with a reduced time to progression of acute myeloid leukemia (AML; HR 2.35; 95% CI, 1.17 to 4.74; P = .017). In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024).
  
  
  CONCLUSIONS
  These results suggest that ASXL1 mutations are frequent molecular aberrations in MDS that predict an adverse prognostic outcome. Screening of patients for ASXL1 mutations might be 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, Carl-Neuberg Str. 1, 30625 Hannover, Germany. thol.felicitas@mh-hannover.de
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.forename: Inna
authors.initials: I
authors.lastname: Friesen
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yun
authors.forename: Eva M
authors.initials: EM
authors.lastname: Weissinger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Anuhar
authors.initials: A
authors.lastname: Chaturvedi
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.forename: Martin
authors.initials: M
authors.lastname: Wichmann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Christiane
authors.initials: C
authors.lastname: Schumann
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000961:Antilymphocyte Serum; D015415:Biomarkers; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D016368:Frameshift Mutation; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D017354:Point Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D012306:Risk
chemical_list: C473949:ASXL1 protein, human; D000961:Antilymphocyte Serum; D015415:Biomarkers; D012333:RNA, Messenger; D012097:Repressor Proteins