Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, 92093, USA.
Department of Computer Science and Engineering, University of California at San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2020 Sep 1;11(1):4374. doi: 10.1038/s41467-020-18099-z.
Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.
癌基因扩增是癌症发病机制的主要驱动因素，通常通过基因组片段的焦点扩增来介导。最近的研究结果表明，染色体外 DNA（ecDNA）是焦点拷贝数扩增（fCNA）的主要驱动因素，它能够促进基因扩增、肿瘤的快速进化以及调控回路的重新布线。解析 fCNA 的结构是揭示其起源机制及其后续生物学后果的第一步。我们引入了一种计算方法，AmpliconReconstructor（AR），用于将长 DNA 片段（>150kb）的光学作图（OM）与下一代测序（NGS）集成，以单核苷酸分辨率解析 fCNA。AR 使用 NGS 衍生的断点图和 OM 支架来生成高保真的重建。通过多种模拟策略验证其性能后，AR 在七种癌细胞系中重建了 fCNA，揭示了 ecDNA 的复杂结构、断裂-融合-桥接和其他复杂重排。通过重建与 fCNA 生成机制相关的重排特征，AR 能够更全面地了解 fCNA 的起源。
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