Chromothripsis in acute myeloid leukemia: biological features and impact on survival
Chromothripsis in acute myeloid leukemia: biological features and impact on survival
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DOI：
10.1038/s41375-018-0035-y
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发表时间：
2018-07-01
期刊：
影响因子：
11.4
通讯作者：
Martinelli, Giovanni
中科院分区：
文献类型：
--
作者：
Fontana, Maria Chiara;Marconi, Giovanni;Martinelli, Giovanni
染色体断裂是由一条或几条染色体在多个片段中断裂而导致的一步基因组破碎灾难，随后随机重新连接和修复。本研究定义了来自三家机构的395名新诊断的成人急性髓性白血病（AML）患者的染色体撕裂发生率、其对生存的影响及其基因组背景。对所有样品进行SNP 6.0或CytoscanHD Array （Affymetrix (R)）检测。我们在26/395例患者中使用自定义算法检测到染色体剥离。染色体thripsis患者具有较高的年龄（p = 0.002）、ELN高风险（p < 0.001）、较低的白细胞（WBC）计数（p = 0.040）、TP53缺失和/或突变（p < 0.001），而FLT3 （p = 0.025）和NPM1 （p = 0.032）突变与染色体thripsis相互排斥。在COX-HR最优回归模型中，与HR患者相比，chromothrysis阳性患者的总生存期（OS） （p < 0.001）较差（p = 0.011），预后较差。染色体断裂表现为染色体不稳定[即TP53改变、5q缺失、较高的拷贝数改变（CNA）均值、复杂的核型、DNA修复和细胞周期的改变]以及染色体4、7、12、16和17的局灶性缺失。CBA。FISH结果显示，染色体断裂与标记染色体、衍生染色体和环染色体有关。综上所述，急性髓性白血病（AML）常发生染色体分裂（6.6%），并影响患者预后和疾病生物学。
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix (R)) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.