Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm
Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm
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DOI：
10.1038/leu.2013.283
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发表时间：
2014-04-01
期刊：
影响因子：
11.4
通讯作者：
Cigudosa, J.
中科院分区：
文献类型：
--
作者：
Menezes, J.;Acquadro, F.;Cigudosa, J.
母细胞浆细胞样树突状细胞肿瘤(BPDCN)是一种非常罕见的疾病，目前缺乏基因组和遗传生物标记物来辅助其临床治疗。我们对3例BPDCN患者进行了全外显子组测序。基于这些数据，我们设计了一种重新测序的方法来识别25个BPDCN样本中38个选定基因的突变。WES发现每个外显子有37-99个有害基因突变，患者之间没有共同的受影响基因，但在分子和疾病途径(血液和皮肤病)方面有明显的重叠。我们首次在人类白血病中发现了IKZF3、HOXB9、UBE2G2和ZEB2的有害突变。靶序列确定了29个复发基因，其患病率从先前已知基因(如TET2)的36%到新发现的基因(如IKZF3或ZEB2)的12%-16%不等。一半的肿瘤具有影响DNA甲基化或染色质重塑途径的突变。临床分析显示，发生甲基化突变的患者总存活率显著降低(P=0.047)。我们首次提供了BPDCN的突变图谱。这些数据支持世卫组织目前将该病归类为髓系疾病，并为纳入表观遗传疗法治疗该病提供了生物学基础。
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P= 0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.