Germline DDX41 mutations define a significant entity within adult MDS/AML patients
Germline DDX41 mutations define a significant entity within adult MDS/AML patients
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DOI：
10.1182/blood.2019000909
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发表时间：
2019-10-24
期刊：
影响因子：
20.3
通讯作者：
Clappier, Emmanuelle
中科院分区：
文献类型：
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作者：
Sebert, Marie;Passet, Marie;Clappier, Emmanuelle
胚系DDX41突变与家族性骨髓增生异常综合征(MDS)和急性髓系白血病(AML)有关。我们分析了1385名MDS或AML患者中与DDX41相关的髓系恶性肿瘤的患病率和特征。使用定向下一代测序，我们在43名无关患者中鉴定了28种不同的种系DDX41变异，我们将其归类为因果变异(n=21)或未知意义变异(n=7)。我们重点研究了33名有因果变异的患者，占我们队列的2.4%。中位年龄为69岁；大多数患者为男性(79%)。只有9名患者(27%)有血液系统恶性肿瘤家族史，15名患者(46%)在MDS/AML诊断前数年有红细胞减少的个人病史。大多数患者核型正常(85%)，最常见的体细胞改变是第二个DDX41突变(79%)。接受强化化疗(n=9)和阿扎替丁(n=11)治疗的高危DDX41 MDS/AML患者总有效率分别为100%和73%，中位总生存期为5.2年。我们的研究强调，胚系DDX41突变在成人MDS/AML中相对常见，通常没有已知的家族史，因此需要进行系统的筛查。与DDX41相关的髓系恶性肿瘤的显著特征包括男性占优势，经常出现先前存在的细胞减少，额外的体细胞DDX41突变，以及相对较好的预后。
Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDSs) and acute myeloid leukemias (AMLs). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients, which we classified as causal (n = 21) or unknown significance (n = 7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. The median age was 69 years; most patients were men (79%). Only 9 patients (27%) had a family history of hematological malignancy, and 15 (46%) had a personal history of cytopenia years before MDS/AML diagnosis. Most patients had a normal karyotype (85%), and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n = 9) or azacitidine (n = 11) had an overall response rate of 100% or 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.