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 Gronroos; 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; Cecile Vicier; Ian P. M. Tomlinson; Priscilla K. Brastianos; Raymond J. Cho; Boris C. Bastian; Lars Dyrskjot; Goran B. Jonsson; 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 Van Loo; Samuel F. Bakhoum; Roland F. Schwarz; Nicholas McGranahan; Charles Swanton

doi:10.1038/s41586-020-2698-6

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 Gronroos, 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 LitchfieldWei 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, Cecile Vicier, Ian P. M. Tomlinson, Priscilla K. Brastianos, Raymond J. Cho, Boris C. Bastian, Lars Dyrskjot, Goran B. Jonsson, 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 Van Loo, Samuel F. Bakhoum, Roland F. Schwarz^*, Nicholas McGranahan^*, Charles Swanton^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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 asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) 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 encompassesBCL9, MCL1andARNT), 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 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) 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.

Original language	English
Pages (from-to)	126-132
Number of pages	29
Journal	Nature
Volume	587
Issue number	7832
Early online date	2 Sept 2020
DOIs	https://doi.org/10.1038/s41586-020-2698-6
Publication status	Published - 5 Nov 2020

Keywords

CANCER
METASTASIS
IDENTIFICATION
EXPRESSION
PATTERNS
GENES
MODEL

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10.1038/s41586-020-2698-6

Cite this

Watkins, T. B. K., Lim, E. L., Petkovic, M., Elizalde, S., Birkbak, N. J., Wilson, G. A., Moore, D. A., Gronroos, E., Rowan, A., Dewhurst, S. M., Demeulemeester, J., Dentro, S. C., Horswell, S., Au, L., Haase, K., Escudero, M., Rosenthal, R., Bakir, M. A., Xu, H., ... Swanton, C. (2020). Pervasive chromosomal instability and karyotype order in tumour evolution. Nature, 587(7832), 126-132. https://doi.org/10.1038/s41586-020-2698-6

@article{051cede1f4614954a1a6ac10cdde6f89,

title = "Pervasive chromosomal instability and karyotype order in tumour evolution",

abstract = "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 asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) 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 encompassesBCL9, MCL1andARNT), 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 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) 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.",

keywords = "CANCER, METASTASIS, IDENTIFICATION, EXPRESSION, PATTERNS, GENES, MODEL",

author = "Watkins, {Thomas B. K.} and Lim, {Emilia L.} and Marina Petkovic and Sergi Elizalde and Birkbak, {Nicolai J.} and Wilson, {Gareth A.} and Moore, {David A.} and Eva Gronroos and Andrew Rowan and Dewhurst, {Sally M.} and Jonas Demeulemeester and Dentro, {Stefan C.} and Stuart Horswell and Lewis Au and Kerstin Haase and Mickael Escudero and Rachel Rosenthal and Bakir, {Maise Al} and Hang Xu and Kevin Litchfield and Lu, {Wei Ting} and Mourikis, {Thanos P.} and Michelle Dietzen and Lavinia Spain and Cresswell, {George D.} and Dhruva Biswas and Philippe Lamy and Iver Nordentoft and Katja Harbst and Francesc Castro-Giner and Yates, {Lucy R.} and Franco Caramia and Fanny Jaulin and Cecile Vicier and Tomlinson, {Ian P. M.} and Brastianos, {Priscilla K.} and Cho, {Raymond J.} and Bastian, {Boris C.} and Lars Dyrskjot and Jonsson, {Goran B.} and Peter Savas and Sherene Loi and Campbell, {Peter J.} and Fabrice Andre and Luscombe, {Nicholas M.} and Neeltje Steeghs and Tjan-Heijnen, {Vivianne C. G.} and Zoltan Szallasi and Samra Turajlic and Mariam Jamal-Hanjani and {Van Loo}, Peter and Bakhoum, {Samuel F.} and Schwarz, {Roland F.} and Nicholas McGranahan and Charles Swanton",

note = "Funding Information: Acknowledgements T.B.K.W. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169) and the Wellcome Trust (FC001169) as well as the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), Breast Cancer Research Foundation (BCRF), Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. E.L.L. receives funding from NovoNordisk Foundation (ID 16584). N.J.B. is a fellow of the Lundbeck Foundation and acknowledges funding from the Aarhus University Research Foundation. E.G. is funded by the European Research Council, FP7-THESEUS-617844 and PROTEUS-835297. J.D. is a postdoctoral fellow of the Research Foundation–Flanders (FWO) and the European Union{\textquoteright}s Horizon 2020 research and innovation program (Marie Sk{\l}odowska-Curie grant agreement no. 703594-DECODE). R.R. is supported by Royal Society Research Professorships Enhancement Award (RP/EA/180007). K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award (grant number MR/ P014712/1). L.Y. was funded by a Wellcome Trust Clinical Career Development Fellowship 214584/Z/18/Z and CRUK Early Detection Pump Prime Award. B.C.B. is supported by an NCI Outstanding Investigatory Award (1R35CA220481). G.B.J. is supported by the Swedish Cancer Society, Swedish Research Council and the Berta Kamprad Foundation. S.L. is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. N.M.L. and G.D.C. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC010110), the UK Medical Research Council (FC010110) and the Wellcome Trust (FC010110). S.T. is funded by Cancer Research UK (grant number C50947/A18176), the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden Hospital and Institute of Cancer Research (grant number A109), the Kidney and Melanoma Cancer Fund of The Royal Marsden Cancer Charity, and The Rosetrees Trust (grant number A2204). M.J.-H. has received funding from Cancer Research UK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Centre. P.V.L. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202) and is a Winton Group Leader in recognition of the Winton Charitable Foundation{\textquoteright}s support towards the establishment of The Francis Crick Institute. S.F.B. is supported by the Office of the Director, the National Institutes of Health under award number DP5OD026395 High-Risk High-Reward Program, the Department of Defense Breast Cancer Research Breakthrough Award W81XWH-16-1-0315 (project: BC151244), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Immunotherapy at MSKCC, the Josie Robertson Foundation and MSKCC core grant P30-CA008748. R.F.S. and M.P. thank the Helmholtz Association (Germany) for support. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is Royal Society Napier Research Professor. His work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorships Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (835297) and Chromavision from the European Union{\textquoteright}s Horizon 2020 research and innovation programme (665233). The results published here are based in part on data generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. The data were retrieved through database of Genotypes and Phenotypes (dbGaP) authorization (accession number phs000178.v9.p8). Information about TCGA and the constituent investigators and institutions of the TCGA research network can be found at http://cancergenome.nih.gov/. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/ L016311/1). In particular, we acknowledge the support of the High-Performance Computing at the Francis Crick Institute as well as the UCL Department of Computer Science Cluster and the support team. This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT-02, NCT01855477) and DRUP clinical study (NCT02925234) have made available to the project. Funding Information: 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). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41586-020-2698-6",

language = "English",

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pages = "126--132",

journal = "Nature",

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Watkins, TBK, Lim, EL, Petkovic, M, Elizalde, S, Birkbak, NJ, Wilson, GA, Moore, DA, Gronroos, E, Rowan, A, Dewhurst, SM, Demeulemeester, J, Dentro, SC, Horswell, S, Au, L, Haase, K, Escudero, M, Rosenthal, R, Bakir, MA, Xu, H, Litchfield, K, Lu, WT, Mourikis, TP, Dietzen, M, Spain, L, Cresswell, GD, Biswas, D, Lamy, P, Nordentoft, I, Harbst, K, Castro-Giner, F, Yates, LR, Caramia, F, Jaulin, F, Vicier, C, Tomlinson, IPM, Brastianos, PK, Cho, RJ, Bastian, BC, Dyrskjot, L, Jonsson, GB, Savas, P, Loi, S, Campbell, PJ, Andre, F, Luscombe, NM, Steeghs, N, Tjan-Heijnen, VCG, Szallasi, Z, Turajlic, S, Jamal-Hanjani, M, Van Loo, P, Bakhoum, SF, Schwarz, RF, McGranahan, N & Swanton, C 2020, 'Pervasive chromosomal instability and karyotype order in tumour evolution', Nature, vol. 587, no. 7832, pp. 126-132. https://doi.org/10.1038/s41586-020-2698-6

TY - JOUR

T1 - Pervasive chromosomal instability and karyotype order in tumour evolution

AU - Watkins, Thomas B. K.

AU - Lim, Emilia L.

AU - Petkovic, Marina

AU - Elizalde, Sergi

AU - Birkbak, Nicolai J.

AU - Wilson, Gareth A.

AU - Moore, David A.

AU - Gronroos, Eva

AU - Rowan, Andrew

AU - Dewhurst, Sally M.

AU - Demeulemeester, Jonas

AU - Dentro, Stefan C.

AU - Horswell, Stuart

AU - Au, Lewis

AU - Haase, Kerstin

AU - Escudero, Mickael

AU - Rosenthal, Rachel

AU - Bakir, Maise Al

AU - Xu, Hang

AU - Litchfield, Kevin

AU - Lu, Wei Ting

AU - Mourikis, Thanos P.

AU - Dietzen, Michelle

AU - Spain, Lavinia

AU - Cresswell, George D.

AU - Biswas, Dhruva

AU - Lamy, Philippe

AU - Nordentoft, Iver

AU - Harbst, Katja

AU - Castro-Giner, Francesc

AU - Yates, Lucy R.

AU - Caramia, Franco

AU - Jaulin, Fanny

AU - Vicier, Cecile

AU - Tomlinson, Ian P. M.

AU - Brastianos, Priscilla K.

AU - Cho, Raymond J.

AU - Bastian, Boris C.

AU - Dyrskjot, Lars

AU - Jonsson, Goran B.

AU - Savas, Peter

AU - Loi, Sherene

AU - Campbell, Peter J.

AU - Andre, Fabrice

AU - Luscombe, Nicholas M.

AU - Steeghs, Neeltje

AU - Tjan-Heijnen, Vivianne C. G.

AU - Szallasi, Zoltan

AU - Turajlic, Samra

AU - Jamal-Hanjani, Mariam

AU - Van Loo, Peter

AU - Bakhoum, Samuel F.

AU - Schwarz, Roland F.

AU - McGranahan, Nicholas

AU - Swanton, Charles

N1 - Funding Information: Acknowledgements T.B.K.W. was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169) and the Wellcome Trust (FC001169) as well as the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), Breast Cancer Research Foundation (BCRF), Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. E.L.L. receives funding from NovoNordisk Foundation (ID 16584). N.J.B. is a fellow of the Lundbeck Foundation and acknowledges funding from the Aarhus University Research Foundation. E.G. is funded by the European Research Council, FP7-THESEUS-617844 and PROTEUS-835297. J.D. is a postdoctoral fellow of the Research Foundation–Flanders (FWO) and the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement no. 703594-DECODE). R.R. is supported by Royal Society Research Professorships Enhancement Award (RP/EA/180007). K.L. is supported by a UK Medical Research Council Skills Development Fellowship Award (grant number MR/ P014712/1). L.Y. was funded by a Wellcome Trust Clinical Career Development Fellowship 214584/Z/18/Z and CRUK Early Detection Pump Prime Award. B.C.B. is supported by an NCI Outstanding Investigatory Award (1R35CA220481). G.B.J. is supported by the Swedish Cancer Society, Swedish Research Council and the Berta Kamprad Foundation. S.L. is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. N.M.L. and G.D.C. were supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC010110), the UK Medical Research Council (FC010110) and the Wellcome Trust (FC010110). S.T. is funded by Cancer Research UK (grant number C50947/A18176), the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden Hospital and Institute of Cancer Research (grant number A109), the Kidney and Melanoma Cancer Fund of The Royal Marsden Cancer Charity, and The Rosetrees Trust (grant number A2204). M.J.-H. has received funding from Cancer Research UK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Centre. P.V.L. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202) and is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. S.F.B. is supported by the Office of the Director, the National Institutes of Health under award number DP5OD026395 High-Risk High-Reward Program, the Department of Defense Breast Cancer Research Breakthrough Award W81XWH-16-1-0315 (project: BC151244), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Immunotherapy at MSKCC, the Josie Robertson Foundation and MSKCC core grant P30-CA008748. R.F.S. and M.P. thank the Helmholtz Association (Germany) for support. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is Royal Society Napier Research Professor. His work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorships Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (835297) and Chromavision from the European Union’s Horizon 2020 research and innovation programme (665233). The results published here are based in part on data generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. The data were retrieved through database of Genotypes and Phenotypes (dbGaP) authorization (accession number phs000178.v9.p8). Information about TCGA and the constituent investigators and institutions of the TCGA research network can be found at http://cancergenome.nih.gov/. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/ L016311/1). In particular, we acknowledge the support of the High-Performance Computing at the Francis Crick Institute as well as the UCL Department of Computer Science Cluster and the support team. This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT-02, NCT01855477) and DRUP clinical study (NCT02925234) have made available to the project. Funding Information: 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). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/11/5

Y1 - 2020/11/5

N2 - 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 asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) 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 encompassesBCL9, MCL1andARNT), 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 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) 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.

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 asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) 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 encompassesBCL9, MCL1andARNT), 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 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) 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.

KW - CANCER

KW - METASTASIS

KW - IDENTIFICATION

KW - EXPRESSION

KW - PATTERNS

KW - GENES

KW - MODEL

U2 - 10.1038/s41586-020-2698-6

DO - 10.1038/s41586-020-2698-6

M3 - Article

C2 - 32879494

SN - 0028-0836

VL - 587

SP - 126

EP - 132

JO - Nature

JF - Nature

IS - 7832

ER -