DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease
DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease
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DOI：
10.1002/ajh.25486
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发表时间：
2019-07-01
影响因子：
12.8
通讯作者：
Patel, Keyur P.
中科院分区：
文献类型：
--
作者：
Quesada, Andres E.;Routbort, Mark J.;Patel, Keyur P.
具有种系DDX 41突变的骨髓肿瘤已纳入2017年WHO分类。描述临床病理特征和突变谱的研究有限。我们在7个月的时间内通过81个基因的下一代测序板检测了具有DDX 41基因突变的骨髓肿瘤。我们确定了34例DDX 41异常的髓系肿瘤患者; 26例（76%）男性和8例女性（24%）[中位年龄，70岁]，20例急性髓系白血病（AML），10例骨髓增生异常综合征（MDS），1例慢性粒单核细胞白血病（CMML）和3例骨髓增生性肿瘤（MPN）。检测到59个DDX 41变异体：27个（46%）出现体细胞突变，32个（54%）可能是种系突变。大多数假定的种系突变位于解旋酶2结构域的上游（93%），并涉及起始密码子的丢失（30%）。大多数体细胞突变在解旋酶2结构域内（78%），其中错义突变p.R525H最常见（67%）。在生殖系或体细胞突变的位置上存在显著差异（P <0.0001）。共检测到19个基因的伴随突变，但只有TP 53（n = 11，32%），ASXL 1（n = 8，24%）和JAK 2（n = 4，12%）是复发性的。20例（59%）患者显示二倍体细胞遗传学。23例（68%）患者表现为AML或MDS-EB-2，表明与高级别髓系肿瘤相关。携带DDX 41突变的髓系肿瘤患者显示男性优势（3：1），就诊时年龄较高，与TP 53突变相关，并与我们在转诊癌症中心设置的队列中的高级别髓系肿瘤相关。这些发现支持DDX 41突变的髓系肿瘤是独特的，需要进行种系确认，并进一步评估家族成员。
Myeloid neoplasms with germline DDX41 mutations have been incorporated into the 2017 WHO classification. Limited studies describing the clinicopathologic features and mutation profile are available. We searched for myeloid neoplasms with a DDX41 gene mutation tested by an 81-gene next-generation sequencing panel over a 7-month period. We identified 34 patients with myeloid neoplasms with DDX41 abnormalities; 26 (76%) men and 8 women (24%) [median age, 70 years], 20 acute myeloid leukemia (AML), 10 myelodysplastic syndrome (MDS), 1 chronic myelomonocytic leukemia (CMML) and 3 myeloproliferative neoplasms (MPN). Fifty-nine DDX41 variants were detected: 27 (46%) appeared somatic and 32 (54%) were presumably germline mutations. The majority of presumed germline mutations were upstream of the Helicase 2 domain (93%) and involved loss of the start codon (30%). The majority of somatic mutations were within the Helicase 2 domain (78%), with the missense mutation p.R525H being most common (67%). There was a significant difference in the location of germline or somatic mutations (P < .0001). Concomitant mutations were detected involving 19 genes, but only TP53 (n = 11, 32%), ASXL1 (n = 8, 24%), and JAK2 (n = 4, 12%) were recurrent. Twenty (59%) patients showed diploid cytogenetics. Twenty-three (68%) patients presented with AML or MDS-EB-2, suggesting an association with high-grade myeloid neoplasm. Patients with myeloid neoplasms carrying DDX41 mutations show male predominance (3:1), higher age at presentation, association with TP53 mutations, and association with high-grade myeloid neoplasms in our cohort at a referral cancer center setting. These findings support the recognition of myeloid neoplasms with DDX41 mutation as unique, need for germline confirmation, and further assessment of family members.