Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.
Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.
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DOI：
10.1084/jem.20110921
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发表时间：
2011-07-04
期刊：
影响因子：
--
通讯作者：
Gaidano G
中科院分区：
文献类型：
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作者：
Fabbri G;Rasi S;Rossi D;Trifonov V;Khiabanian H;Ma J;Grunn A;Fangazio M;Capello D;Monti S;Cresta S;Gargiulo E;Forconi F;Guarini A;Arcaini L;Paulli M;Laurenti L;Larocca LM;Marasca R;Gattei V;Oscier D;Bertoni F;Mullighan CG;Foá R;Pasqualucci L;Rabadan R;Dalla-Favera R;Gaidano G
下一代测序和拷贝数分析有助于深入了解CLL编码基因组的复杂性，并揭示NOTCH1突变激活与不良预后之间的关联。慢性淋巴细胞白血病（CLL）是成人中最常见的白血病，其发病机制在很大程度上仍然未知。在CLL基因组中存在的全部遗传病变，以及因此失调的细胞通路的数量和身份，尚未确定。通过结合下一代测序和拷贝数分析，我们发现典型的CLL编码基因组包含<20个克隆代表的基因改变/病例，包括主要的非沉默突变和较少的拷贝数畸变。这些分析导致在CLL中发现了几个以前不知道的基因被改变。尽管在扩大的CLL筛查队列中，大多数这些基因以低频率受到影响，但在诊断时8.3%的CLL中观察到NOTCH1的突变激活，在疾病向Richter转化的过程中（31.0%）以及在化疗难治性CLL（20.8%）中检测到的频率明显更高。与NOTCH1突变与临床侵袭性疾病形式的关联一致，NOTCH1在CLL诊断时激活成为生存不良的独立预测因子。这些结果提供了CLL编码基因组复杂性的初步数据，并确定了诊断和治疗相关的失调途径。
Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis. The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.
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影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo
DOI：
10.1073/pnas.0801523105
发表时间：
2008-09-02
影响因子：
11.1
作者：
Campbell, Peter J.;Pleasance, Erin D.;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
7.3
作者：
Aster, Jon C.;Blacklow, Stephen C.;Pear, Warren S.
通讯作者：
Pear, Warren S.
影响因子：
30.5
作者：
通讯作者：
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