Pervasive chromosomal instability and karyotype order in tumour evolution

Thomas B. K. Watkins, Emilia L. Lim, Marina Petkovic, Sergi Elizalde, Nicolai J. Birkbak, Gareth A. Wilson, David A. Moore, Eva Grönroos, Andrew Rowan, Sally M. Dewhurst, Jonas Demeulemeester, Stefan C. Dentro, Stuart Horswell, Lewis Au, Kerstin Haase, Mickael Escudero, Rachel Rosenthal, Maise Al Bakir, Hang Xu, Kevin Litchfield, Wei Ting Lu, Thanos P. Mourikis, Michelle Dietzen, Lavinia Spain, George D. Cresswell, Dhruva Biswas, Philippe Lamy, Iver Nordentoft, Katja Harbst, Francesc Castro-Giner, Lucy R. Yates, Franco Caramia, Fanny Jaulin, Cécile Vicier, Ian P. M. Tomlinson, Priscilla K. Brastianos, Raymond J. Cho, Boris C. Bastian, Lars Dyrskjøt, Göran B. Jönsson, Peter Savas, Sherene Loi, Peter J. Campbell, Fabrice Andre, Nicholas M. Luscombe, Neeltje Steeghs, Vivianne C. G. Tjan-Heijnen, Zoltan Szallasi, Samra Turajlic, Mariam Jamal-Hanjani, Peter Loo, Samuel F. Bakhoum, Roland F. Schwarz (), Nicholas McGranahan () and Charles Swanton ()
Additional contact information
Thomas B. K. Watkins: The Francis Crick Institute
Emilia L. Lim: The Francis Crick Institute
Marina Petkovic: Max Delbrück Center for Molecular Medicine
Sergi Elizalde: Dartmouth College
Nicolai J. Birkbak: The Francis Crick Institute
Gareth A. Wilson: The Francis Crick Institute
David A. Moore: University College London Cancer Institute
Eva Grönroos: The Francis Crick Institute
Andrew Rowan: The Francis Crick Institute
Sally M. Dewhurst: Rockefeller University
Jonas Demeulemeester: The Francis Crick Institute
Stefan C. Dentro: The Francis Crick Institute
Stuart Horswell: The Francis Crick Institute
Lewis Au: The Royal Marsden Hospital NHS Foundation Trust
Kerstin Haase: The Francis Crick Institute
Mickael Escudero: The Francis Crick Institute
Rachel Rosenthal: The Francis Crick Institute
Maise Al Bakir: The Francis Crick Institute
Hang Xu: Stanford Cancer Institute
Kevin Litchfield: The Francis Crick Institute
Wei Ting Lu: The Francis Crick Institute
Thanos P. Mourikis: University College London Cancer Institute
Michelle Dietzen: University College London Cancer Institute
Lavinia Spain: The Royal Marsden Hospital NHS Foundation Trust
George D. Cresswell: The Francis Crick Institute
Dhruva Biswas: The Francis Crick Institute
Philippe Lamy: Aarhus University Hospital
Iver Nordentoft: Aarhus University Hospital
Katja Harbst: Lund University
Francesc Castro-Giner: University of Basel and University Hospital Basel
Lucy R. Yates: Wellcome Trust Sanger Institute
Franco Caramia: University of Melbourne
Fanny Jaulin: INSERM U1279, Gustave Roussy
Cécile Vicier: Aix-Marseille University
Ian P. M. Tomlinson: University of Edinburgh
Priscilla K. Brastianos: Broad Institute of Massachusetts Institute of Technology and Harvard
Raymond J. Cho: University of California, San Francisco
Boris C. Bastian: University of California, San Francisco
Lars Dyrskjøt: Aarhus University Hospital
Göran B. Jönsson: Lund University
Peter Savas: University of Melbourne
Sherene Loi: University of Melbourne
Peter J. Campbell: Wellcome Trust Sanger Institute
Fabrice Andre: INSERM U981, PRISM Institute, Gustave Roussy
Nicholas M. Luscombe: The Francis Crick Institute
Neeltje Steeghs: Netherlands Cancer Institute
Vivianne C. G. Tjan-Heijnen: School of GROW, Maastricht University Medical Center
Zoltan Szallasi: Danish Cancer Society Research Center
Samra Turajlic: The Royal Marsden Hospital NHS Foundation Trust
Mariam Jamal-Hanjani: University College London Cancer Institute
Peter Loo: The Francis Crick Institute
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center
Roland F. Schwarz: Max Delbrück Center for Molecular Medicine
Nicholas McGranahan: University College London Cancer Institute
Charles Swanton: The Francis Crick Institute

Nature, 2020, vol. 587, issue 7832, 126-132

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2698-6

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