利用 AmpliconArchitect 探索癌症中的焦点扩增景观。
Exploring the landscape of focal amplifications in cancer using AmpliconArchitect.
机构信息
Department of Computer Science and Engineering, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
Bioinformatics and Systems Biology Program, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
出版信息
Nat Commun. 2019 Jan 23;10(1):392. doi: 10.1038/s41467-018-08200-y.
Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.
焦点癌基因扩增和重排驱动多种癌症类型的肿瘤生长和进化。我们提出了 AmpliconArchitect（AA），这是一种使用全基因组测序（WGS）重建局部扩增区域精细结构的工具，并在多种模拟和真实数据集上进行了广泛验证，涵盖了广泛的覆盖范围和拷贝数。在泛癌数据集上对 AA 重建的扩增子进行分析，揭示了癌症中拷贝数扩增的许多新特性。这些发现支持了一种模型，即由于额外染色体 DNA 的形成和复制，导致焦点扩增的出现。将 AA 应用于 68 种病毒介导的癌症样本，我们发现了大量具有特定结构特征的扩增子，这些特征提示存在混合的、人类-病毒额外染色体 DNA。AA 重建与中期荧光原位杂交（FISH）以及PacBio 测序相结合，在 UPCI：SCC090 细胞系上证实了包含 Forkhead box E1（FOXE1）的杂种扩增子的额外染色体起源和精细结构。
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