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Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2011-05-18)
Felicitas Thol, Inna Friesen, Frederik Damm, Haiyang Yun, Eva M Weissinger, Jürgen Krauter, Katharina Wagner, Anuhar Chaturvedi, Amit Sharma, Martin Wichmann, Gudrun Göhring, Christiane Schumann, Gesine Bug, Oliver Ottmann, Wolf-Karsten Hofmann, Brigitte Schlegelberger, Michael Heuser, Arnold Ganser

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.

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Imprint® Methylated DNA Quantification Kit, To measure global DNA methylation shifts from as low as 10 ng DNA