Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies
Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies
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DOI：
10.1182/blood-2015-10-676098
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发表时间：
2016-02-25
期刊：
影响因子：
20.3
通讯作者：
Scott, Hamish S.
中科院分区：
文献类型：
--
作者：
Lewinsohn, Maya;Brown, Anna L.;Scott, Hamish S.
最近，我们的小组和其他人已经确定了DDX 41突变作为生殖细胞和获得性体细胞突变的家庭与迟发性骨髓增生异常综合征（MDS）和/或急性髓性白血病（AML）的多个案件，这表明DDX 41作为一个肿瘤抑制因子。为了确定新的DDX 41突变是否可以在其他类型的血液系统恶性肿瘤的家庭中确定，我们的小组筛选了两个队列的家庭与不同范围的血液系统恶性肿瘤亚型。在289个家庭中，我们确定了9个（3%）DDX 41突变。如前所述，MDS和AML是最常见的恶性肿瘤，通常为成红细胞亚型，1个家族显示早发性滤泡性淋巴瘤。鉴定了五种新的突变，包括重要功能结构域内的错义突变和预测导致截短蛋白的起始缺失和剪接突变。我们还发现，大多数无症状突变携带者在恶性肿瘤发生前血细胞计数正常。这项研究扩展了在具有种系DDX 41突变的家族中观察到的突变和表型谱。随着越来越多的遗传性和获得性突变在这个基因被确定，DDX 41破坏如何导致血液恶性肿瘤的进一步研究是至关重要的。
Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.