Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype
Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype
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DOI：
10.1182/blood-2011-07-365320
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发表时间：
2011-12-01
期刊：
影响因子：
20.3
通讯作者：
Falini, Brunangelo
中科院分区：
文献类型：
--
作者：
Grossmann, Vera;Tiacci, Enrico;Falini, Brunangelo
在核型正常（CN-AML）的急性髓性白血病（AML）患者中，NPM1和CEBPA突变定义了世界卫生组织2008临时实体，约占患者的60%，但其余40%的患者分子特征不明显。通过对一名缺乏NPM1、CEBPA、FLT3-ITD、IDH1和MLL-PTD突变的CN-AML患者进行全外显子组测序，我们新发现了位于Xp11.4染色体上的BCOR （BCL6协同抑制因子）基因的克隆体细胞突变。对553例AML患者的进一步分析表明，BCOR突变发生在3.8%的未选择的CN-AML患者中，并且代表了相当一部分（17.1%）的CN-AML患者显示出与全外显子组测序的AML指数患者相同的基因型。BCOR体细胞突变为：(1)与种系BCOR突变类似的破坏性事件，导致眼-面-心遗传综合征；(2)与BCOR mRNA水平降低、全长BCOR缺失、截断BCOR蛋白缺失或低表达相关；(3)与NPM1突变几乎互斥；(4)经常与DNMT3A突变相关，表明这些遗传改变之间存在协同性。最后，在422例CN-AML患者队列中，BCOR突变往往与较差的预后相关（2年总生存率为25.6% vs 56.7%; P = 0.032）。我们的研究结果首次揭示了BCOR在CN-AML发病机制中的作用。(血。2011;118 (23):6153 - 6163)
Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardiodental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis. (Blood. 2011;118(23):6153-6163)