Iver Kristiansen Nordentoft

Pervasive chromosomal instability and karyotype order in tumour evolution

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Thomas B.K. Watkins, The Francis Crick Institute
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  • Emilia L. Lim, The Francis Crick Institute, University College London
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  • Marina Petkovic, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
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  • Sergi Elizalde, Dartmouth College
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  • Nicolai J. Birkbak
  • Gareth A. Wilson, The Francis Crick Institute
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  • David A. Moore, University College London
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  • Eva Grönroos, The Francis Crick Institute
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  • Andrew Rowan, The Francis Crick Institute
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  • Sally M. Dewhurst, Rockefeller University
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  • Jonas Demeulemeester, The Francis Crick Institute, KU Leuven
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  • Stefan C. Dentro, The Francis Crick Institute, University of Oxford, Wellcome Sanger Institute
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  • Stuart Horswell, The Francis Crick Institute
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  • Lewis Au, Royal Marsden NHS Foundation Trust, The Francis Crick Institute
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  • Kerstin Haase, The Francis Crick Institute
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  • Mickael Escudero, The Francis Crick Institute
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  • Rachel Rosenthal, The Francis Crick Institute, University College London
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  • Maise Al Bakir, The Francis Crick Institute
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  • Hang Xu, Stanford University
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  • Kevin Litchfield, The Francis Crick Institute
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  • Wei Ting Lu, The Francis Crick Institute
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  • Thanos P. Mourikis, University College London
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  • Michelle Dietzen, University College London
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  • Lavinia Spain, Royal Marsden NHS Foundation Trust, The Francis Crick Institute
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  • George D. Cresswell, The Francis Crick Institute
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  • Dhruva Biswas, The Francis Crick Institute, University College London
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  • Philippe Lamy
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  • Iver Nordentoft
  • Katja Harbst, Lund University
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  • Francesc Castro-Giner, University of Basel, Swiss Institute of Bioinformatics
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  • Lucy R. Yates, Wellcome Sanger Institute, Guy's and St Thomas' NHS Foundation Trust
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  • Franco Caramia, University of Melbourne
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  • Fanny Jaulin, Institut Gustave Roussy
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  • Cécile Vicier, Aix-Marseille Université
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  • Ian P.M. Tomlinson, University of Edinburgh
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  • Priscilla K. Brastianos, Massachusetts Institute of Technology
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  • Raymond J. Cho, University of California at San Francisco
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  • Boris C. Bastian, University of California at San Francisco
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  • Lars Dyrskjøt
  • Göran B. Jönsson, Lund University
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  • Peter Savas, University of Melbourne
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  • Sherene Loi, University of Melbourne
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  • Peter J. Campbell, Wellcome Sanger Institute
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  • Fabrice Andre, Institut Gustave Roussy, Universite Paris-Saclay
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  • Nicholas M. Luscombe, The Francis Crick Institute, University College London, Okinawa Institute of Science and Technology Graduate University
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  • Neeltje Steeghs, Netherlands Cancer Institute
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  • Vivianne C.G. Tjan-Heijnen, Maastricht University
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  • Zoltan Szallasi, Semmelweis University, Boston Children's Hospital, The Danish Cancer Society Research Center
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  • Samra Turajlic, Royal Marsden NHS Foundation Trust, The Francis Crick Institute
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  • Mariam Jamal-Hanjani, University College London
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  • Peter Van Loo, The Francis Crick Institute
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  • Samuel F. Bakhoum, Memorial Sloan-Kettering Cancer Center
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  • Roland F. Schwarz, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, German Cancer Consortium (DKTK), German Cancer Research Center
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  • Nicholas McGranahan, University College London
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  • Charles Swanton, The Francis Crick Institute, University College London

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. 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.

Original languageEnglish
JournalNature
Volume587
Pages (from-to)126-132
Number of pages7
ISSN0028-0836
DOIs
Publication statusPublished - Nov 2020

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