Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing.,Nature Genetics

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Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-02-05 , DOI: 10.1038/s41588-019-0576-7
Isidro Cortés-Ciriano _{1,

2,

3,

4} , Jake June-Koo Lee _{1,

2} , Ruibin Xi ₅ , Dhawal Jain ₁ , Youngsook L Jung ₁ , Lixing Yang _{6,

7} , Dmitry Gordenin ₈ , Leszek J Klimczak ₉ , Cheng-Zhong Zhang _{10,

11} , David S Pellman _{12,

13,

14} , , Peter J Park _{1,

2} ,

Affiliation

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Boston, MA, USA.
Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Cambridge, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China.
Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Durham, NC, USA.
Integrative Bioinformatics Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Durham, NC, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Blavatnik Institute, Boston, MA, USA.
Howard Hughes Medical Institute, Boston, MA, USA.

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

中文翻译：

使用全基因组测序对 2,658 种人类癌症中的染色体碎裂进行综合分析。

染色体碎裂是一种突变现象，其特征是发生在癌症和其他疾病中的大规模、簇状基因组重排。最近对选定癌症类型的研究表明，染色体碎裂可能比最初从低分辨率拷贝数数据推断出的更为常见。在这里，作为国际癌症基因组联盟 (ICGC) 和癌症基因组图谱 (TCGA) 的泛癌症全基因组分析 (PCAWG) 联盟的一部分，我们使用全基因组分析了来自 38 种癌症类型的 2,658 个肿瘤的染色体碎裂模式。基因组测序数据。我们发现，染色体碎裂事件在多种癌症中普遍存在，在几种癌症类型中发生频率超过 50%。尽管典型的染色体碎裂谱显示两个拷贝数状态之间的振荡，但相当一部分事件涉及多个染色体和额外的结构改变。除了非同源末端连接之外，我们还检测复制相关过程和模板插入的签名。染色体碎裂有助于癌基因扩增和基因失活，例如错配修复相关基因。这些发现表明，染色体碎裂是驱动人类癌症基因组进化的一个主要过程。

更新日期：2020-02-05

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