Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer.
Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer.
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DOI：
10.1093/nar/gku590
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发表时间：
2014-08
影响因子：
14.9
通讯作者：
Storlazzi CT
中科院分区：
文献类型：
--
作者：
L'Abbate A;Macchia G;D'Addabbo P;Lonoce A;Tolomeo D;Trombetta D;Kok K;Bartenhagen C;Whelan CW;Palumbo O;Severgnini M;Cifola I;Dugas M;Carella M;De Bellis G;Rocchi M;Carbone L;Storlazzi CT
在癌症中产生双微体染色体（dmin）和均匀染色区域（hsr）的机制仍然知之甚少。通过结合新一代测序，单核苷酸多态性阵列，荧光原位杂交和聚合酶链反应为基础的技术的综合方法，我们推断的精细结构的MYC含有dmin/hsr扩增子窝藏序列从几个不同的染色体在7个肿瘤细胞系，并表征了前所未有的数量的hsr插入位点。局部染色体破碎涉及一个单一的步骤灾难性事件（chromothripsis）最近被提出来解释集群染色体重排和基因组扩增癌症。我们的生物信息学分析的基础上列出的标准，以定义chromothripsis导致我们排除它作为驱动力的扩增子成因在我们的样品。相反，发现共存的异质性扩增子，不同的复杂性和染色体的内容，在细胞系来自同一肿瘤表明发生的多步进化过程中的dmin/hsr。我们的综合方法使我们能够收集MYC扩增子内发生的复杂染色体重排的完整视图，这表明可以调用不止一个模型来解释癌症中dmin/hsr的起源。最后，我们鉴定了PVT 1作为融合事件的靶标，证实了其作为MYC扩增中的断裂点热点的作用。
The mechanism for generating double minutes chromosomes (dmin) and homogeneously staining regions (hsr) in cancer is still poorly understood. Through an integrated approach combining next-generation sequencing, single nucleotide polymorphism array, fluorescent in situ hybridization and polymerase chain reaction-based techniques, we inferred the fine structure of MYC-containing dmin/hsr amplicons harboring sequences from several different chromosomes in seven tumor cell lines, and characterized an unprecedented number of hsr insertion sites. Local chromosome shattering involving a single-step catastrophic event (chromothripsis) was recently proposed to explain clustered chromosomal rearrangements and genomic amplifications in cancer. Our bioinformatics analyses based on the listed criteria to define chromothripsis led us to exclude it as the driving force underlying amplicon genesis in our samples. Instead, the finding of coexisting heterogeneous amplicons, differing in their complexity and chromosome content, in cell lines derived from the same tumor indicated the occurrence of a multi-step evolutionary process in the genesis of dmin/hsr. Our integrated approach allowed us to gather a complete view of the complex chromosome rearrangements occurring within MYC amplicons, suggesting that more than one model may be invoked to explain the origin of dmin/hsr in cancer. Finally, we identified PVT1 as a target of fusion events, confirming its role as breakpoint hotspot in MYC amplification.
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影响因子：
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作者：
Kim, H-P;Cho, G-A;Kim, T-Y
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Kim, T-Y
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CARROLL, SM;DEROSE, ML;WAHL, GM
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WAHL, GM
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Gibaud, Anne;Vogt, Nicolas;Malfoy, Bernard
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Malfoy, Bernard
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Campbell, Peter J.;Stephens, Philip J.;Pleasance, Erin D.;O'Meara, Sarah;Li, Heng;Santarius, Thomas;Stebbings, Lucy A.;Leroy, Catherine;Edkins, Sarah;Hardy, Claire;Teague, Jon W.;Menzies, Andrew;Goodhead, Ian;Turner, Daniel J.;Clee, Christopher M.;Quail, Michael A.;Cox, Antony;Brown, Clive;Durbin, Richard;Hurles, Matthew E.;Edwards, Paul A. W.;Bignell, Graham R.;Stratton, Michael R.;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew