Analyzing Somatic Genome Rearrangements in Human Cancers by Using Whole-Exome Sequencing.
Analyzing Somatic Genome Rearrangements in Human Cancers by Using Whole-Exome Sequencing.
复制标题
DOI：
10.1016/j.ajhg.2016.03.017
复制
发表时间：
2016-05
影响因子：
9.8
通讯作者：
Lixing Yang;Mi-Sook Lee;Hengyu Lu;D. Oh;Yeon Jeong Kim;Donghyun Park;G. Park;X. Ren;C. Bristow;Psalm S. Haseley;Soohyun Lee;A. Pantazi;R. Kucherlapati;W. Park;K. Scott;Yoon-La Choi;P. Park
中科院分区：
文献类型：
--
作者：
Lixing Yang;Mi-Sook Lee;Hengyu Lu;D. Oh;Yeon Jeong Kim;Donghyun Park;G. Park;X. Ren;C. Bristow;Psalm S. Haseley;Soohyun Lee;A. Pantazi;R. Kucherlapati;W. Park;K. Scott;Yoon-La Choi;P. Park
虽然外显子组测序数据主要用于检测单核苷酸变体和插入缺失，但它们也可用于鉴定其断点位于外显子中或附近的基因组重排的子集。使用15种癌症类型中的> 4，600个肿瘤和正常对，我们确定了超过9，000个高置信度的体细胞重排，包括大量的基因融合。我们发现功能性融合的5′端融合伴侣通常是管家基因，而3′端融合伴侣富含酪氨酸激酶。我们通过证明ROR 1-DNAJC 6和CEP 85 L-ROS 1融合体在体外可促进细胞增殖和在体内可促进肿瘤形成，从而确立了ROR 1-DNAJC 6和CEP 85 L-ROS 1融合体的致癌潜力。此外，我们发现约4%的样本存在大量染色体重排，其中许多与ERBB 2和TERT等癌基因的上调有关。尽管从外显子组检测结构改变的灵敏度比从整个基因组检测结构改变的灵敏度低得多，但这种方法对于在癌症和其他疾病中已经产生和将要产生的大量外显子组将是富有成效的。
Although exome sequencing data are generated primarily to detect single-nucleotide variants and indels, they can also be used to identify a subset of genomic rearrangements whose breakpoints are located in or near exons. Using >4,600 tumor and normal pairs across 15 cancer types, we identified over 9,000 high confidence somatic rearrangements, including a large number of gene fusions. We find that the 5′ fusion partners of functional fusions are often housekeeping genes, whereas the 3′ fusion partners are enriched in tyrosine kinases. We establish the oncogenic potential ofROR1-DNAJC6andCEP85L-ROS1fusions by showing that they can promote cell proliferation in vitro and tumor formation in vivo. Furthermore, we found that ∼4% of the samples have massively rearranged chromosomes, many of which are associated with upregulation of oncogenes such asERBB2andTERT. Although the sensitivity of detecting structural alterations from exomes is considerably lower than that from whole genomes, this approach will be fruitful for the multitude of exomes that have been and will be generated, both in cancer and in other diseases.