Pervasive chromosomal instability and karyotype order in tumour evolution,Nature

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Pervasive chromosomal instability and karyotype order in tumour evolution
Nature ( IF 50.5 ) Pub Date : 2020-09-02 , DOI: 10.1038/s41586-020-2698-6
Thomas B K Watkins ₁ , Emilia L Lim _{1,

2} , Marina Petkovic ₃ , Sergi Elizalde ₄ , Nicolai J Birkbak _{1,

5,

6} , Gareth A Wilson ₁ , David A Moore _{2,

7} , Eva Grönroos ₁ , Andrew Rowan ₁ , Sally M Dewhurst ₈ , Jonas Demeulemeester _{9,

10} , Stefan C Dentro _{9,

11,

12} , Stuart Horswell ₁₃ , Lewis Au _{14,

15} , Kerstin Haase ₉ , Mickael Escudero ₁₃ , Rachel Rosenthal _{1,

2,

16} , Maise Al Bakir ₁ , Hang Xu ₁₇ , Kevin Litchfield ₁ , Wei Ting Lu ₁ , Thanos P Mourikis _{2,

18} , Michelle Dietzen _{2,

18} , Lavinia Spain _{14,

15} , George D Cresswell ₁₉ , Dhruva Biswas _{1,

16} , Philippe Lamy ₅ , Iver Nordentoft ₅ , Katja Harbst _{20,

21} , Francesc Castro-Giner _{22,

23} , Lucy R Yates _{24,

25} , Franco Caramia ₂₆ , Fanny Jaulin ₂₇ , Cécile Vicier ₂₈ , Ian P M Tomlinson ₂₉ , Priscilla K Brastianos _{30,

31,

32} , Raymond J Cho ₃₃ , Boris C Bastian _{33,

34,

35} , Lars Dyrskjøt ₅ , Göran B Jönsson _{20,

21} , Peter Savas _{26,

36} , Sherene Loi _{26,

36} , Peter J Campbell ₂₄ , Fabrice Andre _{37,

38,

39} , Nicholas M Luscombe _{19,

40,

41} , Neeltje Steeghs ₄₂ , Vivianne C G Tjan-Heijnen ₄₃ , Zoltan Szallasi _{44,

45,

46} , Samra Turajlic _{14,

15} , Mariam Jamal-Hanjani _{2,

47} , Peter Van Loo ₉ , Samuel F Bakhoum _{48,

49} , Roland F Schwarz _{3,

50,

51} , Nicholas McGranahan _{2,

18} , Charles Swanton _{1,

2,

47}

Affiliation

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Department of Mathematics, Dartmouth College, Hanover, NH, USA.
Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark.
Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark.
Department of Cellular Pathology, University College London Hospitals, London, UK.
Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA.
Cancer Genomics Laboratory, The Francis Crick Institute, London, UK.
Department of Human Genetics, University of Leuven, Leuven, Belgium.
Oxford Big Data Institute, University of Oxford, Oxford, UK.
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
Renal and Skin Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK.
Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK.
Stanford Cancer Institute, Stanford, CA, USA.
Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK.
Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, UK.
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden.
Lund University Cancer Centre, Lund University, Lund, Sweden.
Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland.
Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
Wellcome Trust Sanger Institute, Hinxton, UK.
Department of Clinical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
INSERM U1279, Gustave Roussy, Villejuif, France.
Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.
Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
INSERM U981, PRISM Institute, Gustave Roussy, Villejuif, France.
Department of Medical Oncology, Gustave Roussy, Villejuif, France.
Medical School, Université Paris Saclay, Kremlin Bicetre, France.
UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, London, UK.
Okinawa Institute of Science & Technology, Okinawa, Japan.
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Medical Oncology, School of GROW, Maastricht University Medical Center, Maastricht, The Netherlands.
Danish Cancer Society Research Center, Copenhagen, Denmark.
Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
2nd Department of Pathology, SE-NAP Brain Metastasis Research Group, Semmelweis University, Budapest, Hungary.
Department of Medical Oncology, University College London Hospitals, London, UK.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes 1 , 2 . The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution 1 , 3 , 4 . Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9 , MCL1 , ARNT (also known as HIF1B ), TERT and MYC ) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT ), 5p15.33 ( TERT ), 11q13.3 ( CCND1 ), 19q12 ( CCNE1 ) and 8q24.1 ( MYC ) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC ) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1 ) in HER2 + breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution. Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

中文翻译：

肿瘤进化中普遍存在的染色体不稳定性和核型顺序

癌症中的染色体不稳定性包括 1、2 号染色体数量和结构的动态变化。由此产生的体细胞拷贝数改变 (SCNA) 的多样性可能提供肿瘤进化所需的变异 1 , 3 , 4 。在这里，我们对来自 22 种肿瘤类型的 394 个肿瘤的 1,421 个样本进行多样本定相和 SCNA 分析，以表明持续的染色体不稳定性导致普遍的 SCNA 异质性。 37% 的肿瘤中存在平行进化事件，这些事件会导致不同亚克隆内的相同基因（例如 BCL9、MCL1、ARNT（也称为 HIF1B）、TERT 和 MYC）遭到破坏。大多数复发性丢失可能发生在全基因组加倍之前，在 49% 的肿瘤中发现全基因组加倍是克隆事件。然而，人类白细胞抗原（HLA）基因座杂合性的丧失和 8p 染色体丢失为单个单倍体副本的情况以相当大的亚克隆频率重复出现，甚至在全基因组加倍的肿瘤中也是如此，这表明正在进行的核型重塑。影响染色体 1q21（包括 BCL9、MCL1 和 ARNT）、5p15.33（TERT）、11q13.3（CCND1）、19q12（CCNE1）和 8q24.1（MYC）的局部扩增经常是亚克隆，但似乎是克隆内单个样品。对 1,024 个转移样本的独立系列分析显示，转移样本中富集了 13 个局灶性 SCNA，包括透明细胞肾细胞癌中染色体 8q24.1（包含 MYC）和 HER2 + 乳腺癌中染色体 11q13.3（包含 CCND1）的增加癌症。染色体不稳定性可能使得 SCNA 能够连续选择，这些 SCNA 被确定为在整个肿瘤进化过程中经常并行发生的有序事件。染色体不稳定性使得体细胞拷贝数改变的连续选择成为可能，这些改变被确定为在整个肿瘤进化和转移过程中经常并行发生的有序事件。

更新日期：2020-09-02

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