Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes.

  • Thol F
  • Friesen I
  • Damm F
 et al. 
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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).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.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).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.

Author-supplied keywords

  • 80 and over; Antilymphocyte Serum; Biological Mar
  • Acute
  • Adult; Aged; Aged
  • MHC Class II; Humans; Kaplan-Meier Estimate; Leuk
  • Messenger
  • Myeloid
  • analysis/biosynthesis/genetics; Risk
  • biosynthesis; Repressor Proteins
  • epidemiology; Male; Middle Aged; Multicenter Stud
  • genetics/mortality/therapy; Point Mutation; Progn
  • genetics; Female; Follow-Up Studies; Frameshift M
  • statistics /&/ numerical data; DNA Methylation; D
  • statistics /&/ numerical data; Myelodysplastic Sy

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  • Felicitas Thol

  • Inna Friesen

  • Frederik Damm

  • Haiyang Yun

  • Eva M Weissinger

  • J�rgen Krauter

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