Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
N Engl J Med. 2011 Jun 30;364(26):2496-506. doi: 10.1056/NEJMoa1013343.
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.).
骨髓增生异常综合征是一种临床异质性疾病,其特征为克隆性造血、分化障碍、外周血细胞减少以及向急性髓系白血病进展的风险。体细胞突变可能影响临床表型,但目前的预后评分系统并不包括这些突变。
我们采用包括下一代测序和基于质谱的基因分型在内的基因组学方法,鉴定了 439 例骨髓增生异常综合征患者骨髓抽吸样本中的基因突变。然后,我们检查了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、骨髓原始细胞比例和总生存期。
我们共鉴定出 18 个基因的体细胞突变,其中包括 ETV6 和 GNAS 两个之前未报道在骨髓增生异常综合征患者中发生突变的基因。所有患者中有 51%至少存在一个点突变,其中核型正常的患者占 52%。RUNX1、TP53 和 NRAS 的突变与严重血小板减少(所有比较的 P<0.001)和骨髓原始细胞比例增加(所有比较的 P<0.006)关系最为密切。在多变量 Cox 回归模型中,5 个基因的突变存在独立的预后意义:TP53(任何原因死亡的风险比,2.48;95%置信区间[CI],1.60 至 3.84)、EZH2(风险比,2.13;95%CI,1.36 至 3.33)、ETV6(风险比,2.04;95%CI,1.08 至 3.86)、RUNX1(风险比,1.47;95%CI,1.01 至 2.15)和 ASXL1(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,与特定的临床特征相关。TP53、EZH2、ETV6、RUNX1 和 ASXL1 的突变是骨髓增生异常综合征患者总生存期不良的预测因子,独立于已确立的危险因素。(由美国国立卫生研究院等资助)。