PMID- 32879494 OWN - NLM STAT- MEDLINE DCOM- 20210218 LR - 20240210 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 587 IP - 7832 DP - 2020 Nov TI - Pervasive chromosomal instability and karyotype order in tumour evolution. PG - 126-132 LID - 10.1038/s41586-020-2698-6 [doi] AB - 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. FAU - Watkins, Thomas B K AU - Watkins TBK AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Lim, Emilia L AU - Lim EL AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. FAU - Petkovic, Marina AU - Petkovic M AUID- ORCID: 0000-0003-2875-216X AD - Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, Germany. FAU - Elizalde, Sergi AU - Elizalde S AUID- ORCID: 0000-0003-4116-2455 AD - Department of Mathematics, Dartmouth College, Hanover, NH, USA. FAU - Birkbak, Nicolai J AU - Birkbak NJ AUID- ORCID: 0000-0003-1613-9587 AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. AD - Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark. AD - Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark. FAU - Wilson, Gareth A AU - Wilson GA AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Moore, David A AU - Moore DA AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. AD - Department of Cellular Pathology, University College London Hospitals, London, UK. FAU - Gronroos, Eva AU - Gronroos E AUID- ORCID: 0000-0001-8303-5409 AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Rowan, Andrew AU - Rowan A AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Dewhurst, Sally M AU - Dewhurst SM AD - Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY, USA. FAU - Demeulemeester, Jonas AU - Demeulemeester J AUID- ORCID: 0000-0002-2660-2478 AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. AD - Department of Human Genetics, University of Leuven, Leuven, Belgium. FAU - Dentro, Stefan C AU - Dentro SC AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. AD - Oxford Big Data Institute, University of Oxford, Oxford, UK. AD - Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. FAU - Horswell, Stuart AU - Horswell S AUID- ORCID: 0000-0003-2787-1933 AD - Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK. FAU - Au, Lewis AU - Au L AD - Renal and Skin Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK. AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. FAU - Haase, Kerstin AU - Haase K AUID- ORCID: 0000-0002-0944-5618 AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. FAU - Escudero, Mickael AU - Escudero M AUID- ORCID: 0000-0002-1336-815X AD - Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK. FAU - Rosenthal, Rachel AU - Rosenthal R AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. AD - Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK. FAU - Bakir, Maise Al AU - Bakir MA AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Xu, Hang AU - Xu H AD - Stanford Cancer Institute, Stanford, CA, USA. FAU - Litchfield, Kevin AU - Litchfield K AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Lu, Wei Ting AU - Lu WT AUID- ORCID: 0000-0002-1405-4806 AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. FAU - Mourikis, Thanos P AU - Mourikis TP AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. AD - Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. FAU - Dietzen, Michelle AU - Dietzen M AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. AD - Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. FAU - Spain, Lavinia AU - Spain L AD - Renal and Skin Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK. AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. FAU - Cresswell, George D AU - Cresswell GD AUID- ORCID: 0000-0003-3303-068X AD - Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, UK. FAU - Biswas, Dhruva AU - Biswas D AUID- ORCID: 0000-0001-9141-5188 AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. AD - Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK. FAU - Lamy, Philippe AU - Lamy P AD - Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark. FAU - Nordentoft, Iver AU - Nordentoft I AD - Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark. FAU - Harbst, Katja AU - Harbst K AUID- ORCID: 0000-0002-8225-1510 AD - Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden. AD - Lund University Cancer Centre, Lund University, Lund, Sweden. FAU - Castro-Giner, Francesc AU - Castro-Giner F AUID- ORCID: 0000-0001-6111-0754 AD - Department of Biomedicine, Cancer Metastasis Laboratory, University of Basel and University Hospital Basel, Basel, Switzerland. AD - Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. FAU - Yates, Lucy R AU - Yates LR AD - Wellcome Trust Sanger Institute, Hinxton, UK. AD - Department of Clinical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK. FAU - Caramia, Franco AU - Caramia F AUID- ORCID: 0000-0002-5086-2544 AD - Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. FAU - Jaulin, Fanny AU - Jaulin F AUID- ORCID: 0000-0002-5110-1800 AD - INSERM U1279, Gustave Roussy, Villejuif, France. FAU - Vicier, Cecile AU - Vicier C AD - Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France. FAU - Tomlinson, Ian P M AU - Tomlinson IPM AD - Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK. FAU - Brastianos, Priscilla K AU - Brastianos PK AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. AD - Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. AD - Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. FAU - Cho, Raymond J AU - Cho RJ AUID- ORCID: 0000-0001-6090-6603 AD - Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. FAU - Bastian, Boris C AU - Bastian BC AUID- ORCID: 0000-0003-1836-6062 AD - Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA. AD - Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. AD - Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. FAU - Dyrskjot, Lars AU - Dyrskjot L AUID- ORCID: 0000-0001-7061-9851 AD - Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark. FAU - Jonsson, Goran B AU - Jonsson GB AD - Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden. AD - Lund University Cancer Centre, Lund University, Lund, Sweden. FAU - Savas, Peter AU - Savas P AUID- ORCID: 0000-0001-5999-428X AD - Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. FAU - Loi, Sherene AU - Loi S AUID- ORCID: 0000-0001-6137-9171 AD - Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia. AD - Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. FAU - Campbell, Peter J AU - Campbell PJ AUID- ORCID: 0000-0002-3921-0510 AD - Wellcome Trust Sanger Institute, Hinxton, UK. FAU - Andre, Fabrice AU - Andre F AUID- ORCID: 0000-0001-5795-8357 AD - INSERM U981, PRISM Institute, Gustave Roussy, Villejuif, France. AD - Department of Medical Oncology, Gustave Roussy, Villejuif, France. AD - Medical School, Universite Paris Saclay, Kremlin Bicetre, France. FAU - Luscombe, Nicholas M AU - Luscombe NM AUID- ORCID: 0000-0001-5293-4778 AD - Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, UK. AD - UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, London, UK. AD - Okinawa Institute of Science & Technology, Okinawa, Japan. FAU - Steeghs, Neeltje AU - Steeghs N AD - Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. FAU - Tjan-Heijnen, Vivianne C G AU - Tjan-Heijnen VCG AD - Department of Medical Oncology, School of GROW, Maastricht University Medical Center, Maastricht, The Netherlands. FAU - Szallasi, Zoltan AU - Szallasi Z AD - Danish Cancer Society Research Center, Copenhagen, Denmark. AD - Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. AD - 2nd Department of Pathology, SE-NAP Brain Metastasis Research Group, Semmelweis University, Budapest, Hungary. FAU - Turajlic, Samra AU - Turajlic S AUID- ORCID: 0000-0001-8846-136X AD - Renal and Skin Units, The Royal Marsden Hospital NHS Foundation Trust, London, UK. AD - Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. FAU - Jamal-Hanjani, Mariam AU - Jamal-Hanjani M AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. AD - Department of Medical Oncology, University College London Hospitals, London, UK. FAU - Van Loo, Peter AU - Van Loo P AUID- ORCID: 0000-0003-0292-1949 AD - Cancer Genomics Laboratory, The Francis Crick Institute, London, UK. FAU - Bakhoum, Samuel F AU - Bakhoum SF AD - Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. AD - Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Schwarz, Roland F AU - Schwarz RF AUID- ORCID: 0000-0001-9155-4268 AD - Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, Germany. roland.schwarz@mdc-berlin.de. AD - German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany. roland.schwarz@mdc-berlin.de. AD - German Cancer Research Center (DKFZ), Heidelberg, Germany. roland.schwarz@mdc-berlin.de. FAU - McGranahan, Nicholas AU - McGranahan N AUID- ORCID: 0000-0001-9537-4045 AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. nicholas.mcgranahan.10@ucl.ac.uk. AD - Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK. nicholas.mcgranahan.10@ucl.ac.uk. FAU - Swanton, Charles AU - Swanton C AUID- ORCID: 0000-0002-4299-3018 AD - Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. charles.swanton@crick.ac.uk. AD - Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. charles.swanton@crick.ac.uk. AD - Department of Medical Oncology, University College London Hospitals, London, UK. charles.swanton@crick.ac.uk. LA - eng GR - FC001169/CRUK_/Cancer Research UK/United Kingdom GR - FC001110/CRUK_/Cancer Research UK/United Kingdom GR - 214584/Z/18/Z/WT_/Wellcome Trust/United Kingdom GR - FC001169/WT_/Wellcome Trust/United Kingdom GR - DP5 OD026395/OD/NIH HHS/United States GR - 29911/CRUK_/Cancer Research UK/United Kingdom GR - 21999/CRUK_/Cancer Research UK/United Kingdom GR - MR/P014712/1/MRC_/Medical Research Council/United Kingdom GR - FC001202/MRC_/Medical Research Council/United Kingdom GR - FC001202/CRUK_/Cancer Research UK/United Kingdom GR - FC001169/MRC_/Medical Research Council/United Kingdom GR - 211179/Z/18/Z/WT_/Wellcome Trust/United Kingdom GR - ERC_/European Research Council/International GR - FC010110/WT_/Wellcome Trust/United Kingdom GR - 18176/CRUK_/Cancer Research UK/United Kingdom GR - FC001110/WT_/Wellcome Trust/United Kingdom GR - P30 CA008748/CA/NCI NIH HHS/United States GR - MR/L016311/1/MRC_/Medical Research Council/United Kingdom GR - FC001202/ARC_/Arthritis Research UK/United Kingdom GR - FC001110/MRC_/Medical Research Council/United Kingdom GR - FC001169/ARC_/Arthritis Research UK/United Kingdom GR - 24956/CRUK_/Cancer Research UK/United Kingdom GR - R01 CA256188/CA/NCI NIH HHS/United States GR - 20466/CRUK_/Cancer Research UK/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - FC001202/WT_/Wellcome Trust/United Kingdom GR - 17786/CRUK_/Cancer Research UK/United Kingdom GR - R35 CA220481/CA/NCI NIH HHS/United States GR - MR/P014712/2/MRC_/Medical Research Council/United Kingdom GR - 30025/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200902 PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (CCNE1 protein, human) RN - 0 (Cyclin E) RN - 0 (Oncogene Proteins) SB - IM MH - Chromosomal Instability/*genetics MH - Chromosomes, Human, Pair 11/genetics MH - Chromosomes, Human, Pair 8/genetics MH - Clone Cells/metabolism/pathology MH - Cyclin E/genetics MH - DNA Copy Number Variations/genetics MH - *Evolution, Molecular MH - Female MH - Humans MH - *Karyotype MH - Loss of Heterozygosity/genetics MH - Male MH - Mutagenesis MH - Neoplasm Metastasis/*genetics/pathology MH - Neoplasms/*genetics/pathology MH - Oncogene Proteins/genetics PMC - PMC7611706 MID - EMS133948 COIS- Competing interests G.A.W. has consulted for and has stock options in Achilles Therapeutics. D.A.M. reports speaker fees from AstraZeneca. M.A.B. has consulted for Achilles Therapeutics. C.V. has received travel expenses from Astellas, Roche and Pfizer, and grant support from Bristol Myers Squibb. R.R. has consulted for and has stock options in Achilles Therapeutics. K.L. reports speaker fees from Roche Tissue Diagnostics. P.K.B. has consulted for Angiochem, Roche-Genentech, Eli Lilly, Tesaro, ElevateBio, Pfizer (Array), and received grant or research support from Merck, Bristol Myers Squibb and Eli Lilly and honoraria from Merck, Roche-Genentech and Eli Lilly. L.D. has sponsored research agreements with C2i-genomics, Natera, AstraZeneca and Ferring, and has an advisory/consulting role at Ferring. P.S. serves an uncompensated consultant for Roche-Genentech. S.L. receives research funding to her institution from Novartis, Bristol Myers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, Eli Lilly and Seattle Genetics, has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, Bristol Myers Squibb, Merck, AstraZeneca and Roche-Genentech and has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline and G1 Therapeutics. F.A. is a member of the Advisory Boards for Pfizer, AstraZeneca, Eli Lilly, Roche-Genentech, Novartis and Daiichi Sankyo, acknowledges grant support from Pfizer, AstraZeneca, Eli Lilly, Novartis and Daiichi Sankyo and is a co-founder of Pegacsy. V.C.G.T.-H. reports grants and personal fees from Pfizer, Roche, Novartis and Eli Lilly, grants from Eisai and personal fees from Accord. S.T. has received funding from Ventana Medical Systems Inc (grant numbers 10467 and 10530), has received speaking fees from Roche, AstraZeneca, Novartis and Ipsen and has the following European and US patent filed: Indel mutations as a therapeutic target and predictive biomarker (PCTGB2018/051892) and European patent: Clear Cell Renal Cell Carcinoma Biomarkers (P113326GB). M.J.-H. is a member of the Advisory Board for Achilles Therapeutics. S.F.B. holds a patent related to some of the work described targeting CIN and the cGAS-STING pathway in advanced cancer, owns equity in, receives compensation from and serves as a consultant and on the Scientific Advisory Board and Board of Directors of Volastra Therapeutics, and has also consulted for Sanofi, received sponsored travel from the Prostate Cancer Foundation, and both travel and compensation from Cancer Research UK. N.M. has stock options in and has consulted for Achilles Therapeutics and holds a European patent in determining HLA LOH (PCT/GB2018/052004). C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical, is an AstraZeneca Advisory Board Member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds European patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). EDAT- 2020/09/04 06:00 MHDA- 2021/02/20 06:00 PMCR- 2021/09/24 CRDT- 2020/09/04 06:00 PHST- 2019/04/01 00:00 [received] PHST- 2020/06/24 00:00 [accepted] PHST- 2020/09/04 06:00 [pubmed] PHST- 2021/02/20 06:00 [medline] PHST- 2020/09/04 06:00 [entrez] PHST- 2021/09/24 00:00 [pmc-release] AID - 10.1038/s41586-020-2698-6 [pii] AID - 10.1038/s41586-020-2698-6 [doi] PST - ppublish SO - Nature. 2020 Nov;587(7832):126-132. doi: 10.1038/s41586-020-2698-6. Epub 2020 Sep 2.