Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia
Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia
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DOI：
10.1182/blood-2014-03-560227
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发表时间：
2014-08-28
期刊：
影响因子：
20.3
通讯作者：
Cazzola, Mario
中科院分区：
文献类型：
--
作者：
Malcovati, Luca;Papaemmanuil, Elli;Cazzola, Mario
我们对骨髓增生异常综合征（MDS）和骨髓增生异常/骨髓增生性肿瘤（MDS/MPN）的遗传基础的了解已经大大提高。为了确定临床相关性的基因型/表型关系，我们研究了308例MDS、MDS/MPN或从MDS演变而来的急性髓系白血病患者。无监督统计分析，包括世界卫生组织分类标准和体细胞突变，显示与sf3b1突变相关的MDS（245例患者中51例，20.8%）是一个独特的病毒学实体，与当前的形态学分类标准无关。相反，具有非突变SF3B1的环状铁母细胞的MDS与其他MDS亚型在不同的集群中分离。参与DNA甲基化的基因、SF3B1以外的剪接因子、RAS通路和黏结蛋白复合体基因的突变与多谱系发育不良独立相关，并确定了一个不同的亚群（245例患者中有51例，20.8%）。没有复发性突变模式与单系发育不良相关，不含环状铁母细胞。不考虑驱动体细胞突变，5%的骨髓母细胞阈值保留了识别克隆进化病例的显著区别值。TET2和SRSF2的检测可高度预测以骨髓增生异常和单核细胞增多为特征的髓系肿瘤，包括但不限于慢性髓系白血病。这些结果证明髓系肿瘤的分子分类是可行的。
Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. Todefine genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.