Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
J Clin Oncol. 2011 Jun 20;29(18):2499-506. doi: 10.1200/JCO.2010.33.4938. Epub 2011 May 16.
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).
PATIENTS, MATERIALS, AND 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.
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.
研究在一大群骨髓增生异常综合征（MDS）患者中，额外性 sex comb 样 1（ASXL1）突变的发生率和预后影响。
患者、材料和方法：通过直接测序，共检查了 193 例 MDS 患者和 65 例健康志愿者的 ASXL1 突变情况，并检查了 ASXL1 的表达水平。根据其他临床和分子预后标志物，评估 ASXL1 突变和表达水平的预后影响。
ASXL1 突变在 MDS 中的发生率为 20.7%（n=40/193），70%（n=28）为移码突变，30%（n=12）为杂合点突变导致翻译改变。ASXL1 突变与中危核型相关（P=0.002），但与其他临床参数无关。ASXL1 突变的存在与所有患者（HR，1.744；95%CI，1.08 至 2.82；P=0.024）和仅存在移码突变患者（HR，2.06；95%CI，1.21 至 3.50；P=0.008）的总生存期较短相关。ASXL1 移码突变与急性髓系白血病（AML）进展时间缩短相关（HR 2.35；95%CI，1.17 至 4.74；P=0.017）。在多变量分析中，当考虑核型、输血依赖性和 IDH1 突变状态时，ASXL1 移码突变在 MDS 中仍然是一个独立的预后标志物（总生存期：HR，1.85；95%CI，1.03 至 3.34；P=0.040；向 AML 进展时间：HR，2.39；95%CI，1.12 至 5.09；P=0.024）。
这些结果表明，ASXL1 突变是 MDS 中常见的分子异常，可预测不良预后。对患者进行 ASXL1 突变筛查可能有助于未来的临床危险分层和治疗决策。
