Clinical effect of point mutations in myelodysplastic syndromes.
Clinical effect of point mutations in myelodysplastic syndromes.
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DOI：
10.1056/nejmoa1013343
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发表时间：
2011-06-30
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影响因子：
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通讯作者：
Ebert BL
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作者：
Bejar R;Stevenson K;Abdel-Wahab O;Galili N;Nilsson B;Garcia-Manero G;Kantarjian H;Raza A;Levine RL;Neuberg D;Ebert BL
骨髓增生异常综合征是临床异质性疾病，其特征在于克隆性造血、分化受损、外周血细胞减少和进展为急性髓性白血病的风险。体细胞突变可能影响临床表型，但不包括在目前的预后评分系统。我们使用了基因组方法的组合，包括下一代测序和基于质谱的基因分型，以确定439例骨髓增生异常综合征患者骨髓穿刺样本中的突变。然后，我们检查每个基因的突变状态是否与临床变量相关，包括特定的血细胞减少，原始细胞比例和总生存率。我们在18个基因中发现了体细胞突变，包括ETV 6和GNAS两个，这些基因在骨髓增生异常综合征患者中尚未报道过突变。共有51%的患者至少有一个点突变，包括52%的细胞遗传学正常的患者。RUNX 1、TP 53和NRAS突变与重度血小板减少症（所有比较P<0.001）和骨髓原始细胞比例增加（所有比较P<0.006）相关性最强。在多变量考克斯回归模型中，五个基因突变的存在保留了独立的预后意义：TP 53（全因死亡的风险比，2.48; 95%置信区间[CI]，1.60 - 3.84），EZH 2（风险比，2.13; 95% CI，1.36 - 3.33），ETV 6（风险比，2.04; 95% CI，1.08至3.86）、RUNX 1（风险比，1.47; 95% CI，1.01至2.15）和ASXL 1（风险比，1.38; 95% CI，1.00至1.89）。体细胞点突变在骨髓增生异常综合征中很常见，并与特定的临床特征相关。TP 53、EZH 2、ETV 6、RUNX 1和ASXL 1基因突变是骨髓增生异常综合征患者总生存率低的预测因子，与已确定的风险因素无关。（由美国国立卫生研究院和其他机构资助。
Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry–based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.)