Bell John M, Lau Billy T, Greer Stephanie U, Wood-Bouwens Christina, Xia Li C, Connolly Ian D, Gephart Melanie H, Ji Hanlee P
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Nucleic Acids Res. 2017 Nov 2;45(19):e162. doi: 10.1093/nar/gkx712.
Genomic instability is a frequently occurring feature of cancer that involves large-scale structural alterations. These somatic changes in chromosome structure include duplication of entire chromosome arms and aneuploidy where chromosomes are duplicated beyond normal diploid content. However, the accurate determination of aneuploidy events in cancer genomes is a challenge. Recent advances in sequencing technology allow the characterization of haplotypes that extend megabases along the human genome using high molecular weight (HMW) DNA. For this study, we employed a library preparation method in which sequence reads have barcodes linked to single HMW DNA molecules. Barcode-linked reads are used to generate extended haplotypes on the order of megabases. We developed a method that leverages haplotypes to identify chromosomal segmental alterations in cancer and uses this information to join haplotypes together, thus extending the range of phased variants. With this approach, we identified mega-haplotypes that encompass entire chromosome arms. We characterized the chromosomal arm changes and aneuploidy events in a manner that offers similar information as a traditional karyotype but with the benefit of DNA sequence resolution. We applied this approach to characterize aneuploidy and chromosomal alterations from a series of primary colorectal cancers.
基因组不稳定是癌症中经常出现的特征，涉及大规模结构改变。染色体结构中的这些体细胞变化包括整条染色体臂的重复以及非整倍体现象，即染色体的复制超过了正常二倍体含量。然而，准确确定癌症基因组中的非整倍体事件是一项挑战。测序技术的最新进展使得能够利用高分子量（HMW）DNA对沿人类基因组延伸数百万碱基的单倍型进行表征。在本研究中，我们采用了一种文库制备方法，其中序列读数带有与单个HMW DNA分子相连的条形码。与条形码相连的读数用于生成数百万碱基级别的延伸单倍型。我们开发了一种方法，利用单倍型来识别癌症中的染色体片段改变，并利用这些信息将单倍型连接在一起，从而扩展了分型变异的范围。通过这种方法，我们鉴定出了包含整条染色体臂的巨型单倍型。我们以一种提供与传统核型类似信息但具有DNA序列分辨率优势的方式，对染色体臂变化和非整倍体事件进行了表征。我们应用这种方法对一系列原发性结直肠癌的非整倍体和染色体改变进行了表征。
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