Recurrent genetic defects on chromosome 5q in myeloid neoplasms.
Recurrent genetic defects on chromosome 5q in myeloid neoplasms.
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DOI：
10.18632/oncotarget.14130
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发表时间：
2017-01-24
期刊：
影响因子：
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通讯作者：
Maciejewski JP
中科院分区：
文献类型：
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作者：
Hosono N;Makishima H;Mahfouz R;Przychodzen B;Yoshida K;Jerez A;LaFramboise T;Polprasert C;Clemente MJ;Shiraishi Y;Chiba K;Tanaka H;Miyano S;Sanada M;Cui E;Verma AK;McDevitt MA;List AF;Saunthararajah Y;Sekeres MA;Boultwood J;Ogawa S;Maciejewski JP
染色体5 q缺失（del（5 q））是骨髓性肿瘤中最常见的核型异常。为了确定与del（5 q）相关的致病分子特征，将下一代测序应用于133例骨髓肿瘤患者（MDS; N = 69，MDS/MPN; N = 5，sAML; N = 29，pAML; N = 30），其中del（5 q）作为唯一异常或复杂核型的一部分，并将结果与患者二倍体chr 5的分子特征进行比较。鉴定了一些具有单倍表达不足和/或复发性体细胞突变的5 q基因;对于这些基因，通常缺失的5 q区域内的CSNK 1A 1和G3 BP 1以及通常保留区域内的DDX 41最常受体细胞突变的影响。这些基因在缺失病例中表现出一致的单倍不足; G3 BP 1或DDX 41的低表达/突变与生存率差相关，可能是由于细胞功能降低。del（5 q）患者其他染色体上最常见的突变包括TP 53，FLT 3（ITD或TKD），NPM 1或TET 2突变，并且相互排斥。连续测序允许定义克隆结构和动力学，在具有外显子组测序的患者中，信息性SNP的等位基因不平衡促进del（5 q）的克隆大小和体细胞突变的克隆负荷的同时近似。我们的研究结果阐明了del（5 q）的分子缺陷特征，其临床影响和逐步演变的继承谱。
Deletion of chromosome 5q (del(5q)) is the most common karyotypic abnormality in myeloid neoplasms. To define the pathogenic molecular features associated with del(5q), next–generation sequencing was applied to 133 patients with myeloid neoplasms (MDS; N = 69, MDS/MPN; N = 5, sAML; N = 29, pAML; N = 30) with del(5q) as a sole abnormally or a part of complex karyotype and results were compared to molecular features of patients diploid for chr5. A number of 5q genes with haploinsufficient expression and/or recurrent somatic mutations were identified; for these genes, CSNK1A1 and G3BP1 within the commonly deleted 5q region and DDX41 within a commonly retained region were most commonly affected by somatic mutations. These genes showed consistent haploinsufficiency in deleted cases; low expression/mutations of G3BP1 or DDX41 were associated with poor survival, likely due to decreased cellular function. The most common mutations on other chromosomes in patients with del(5q) included TP53, and mutations of FLT3 (ITD or TKD), NPM1 or TET2 and were mutually exclusive. Serial sequencing allowed for definition of clonal architecture and dynamics, in patients with exome sequencing allelic imbalance for informative SNPs facilitated simultaneous approximation of clonal size of del(5q) and clonal burden for somatic mutations. Our results illuminate the spectrum of molecular defects characteristic of del(5q), their clinical impact and succession of stepwise evolution.