Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer

William C H Cross; Salpie Nowinski; George D Cresswell; Maximilian Mossner; Abhirup Banerjee; Bingxin Lu; Marc J Williams; Georgios Vlachogiannis; Laura J Gay; Ann-Marie Baker; Christopher Kimberley; Frederick J H Whiting; Hayley L Belnoue-Davis; Pierre Martinez; Maria Traki; Viola Walther; Kane Smith; Javier Fernandez-Mateos; Erika Yara-Romero; Erica A Oliveira; Salvatore Milite; Giulio Caravagna; Chela T James; George Elia; Alison Berner; Chang-Ho Ryan Choi; Pradeep Ramagiri; Ritika Chauhan; Nik Matthews; Jamie Murphy; Anthony Antoniou; Susan K Clark; Miriam Mitchison; Jo-Anne Chin Aleong; Enric Domingo; Inmaculada Spiteri; Stuart A C McDonald; Darryl Shibata; Miangela M Laclé; Lai Mun Wang; Morgan Moorghen; Ian P M Tomlinson; Marco Novelli; Marnix Jansen; Alan Watson; Nicola Valeri; Nicholas A Wright; John A Bridgewater; Manuel Rodriguez-Justo; Chris P Barnes; Hemant M Kocher; Simon J Leedham; Andrea Sottoriva; Trevor A Graham

doi:10.1158/2159-8290.CD-24-0813

Journal article

Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer

William C H Cross, Salpie Nowinski, George D Cresswell, Maximilian Mossner, Abhirup Banerjee, Bingxin Lu, Marc J Williams, Georgios Vlachogiannis, Laura J Gay, Ann-Marie Baker, …

Cancer discovery, p.OF1

21/01/2026

DOI: https://doi.org/10.1158/2159-8290.CD-24-0813

PMID: 41563072

Abstract

Aneuploidy is near-ubiquitous in cancer and contributes to tumor biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterized. We performed longitudinal genomic analysis of 755 samples from 167 patients with colorectal-derived neoplasias from different stages through metastasis and treatment. Adenomas had few copy number alterations (CNA) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual colorectal cancer glands from the same tumor had similar karyotypes, despite evidence of ongoing instability at the cell level. CNAs in metastatic lesions, after therapy, and in late recurrences were similar to the primary. Mathematical modeling indicated that these data are consistent with the action of negative selection on CNAs that "trap" cancer genomes on a fitness peak characterized by specific CNAs. Hence, progression to colorectal cancer requires traversing a rugged fitness landscape, whereas subsequent CNA evolution is constrained by negative selection. We profiled 167 long-term responders longitudinally (755 samples), documenting long-term cancer evolution. We found that a genetic bottleneck is required for progression and is associated with dramatic increase in CNAs but decrease in clonal diversity. After initiation, copy number evolution is constrained by negative selection through metastasis and treatment.

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Title: Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer
Creators: William C H Cross - University of Reading
Salpie Nowinski - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
George D Cresswell - St. Anna Children's Cancer Research Institute
Maximilian Mossner - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Abhirup Banerjee - Queen Mary University of London
Bingxin Lu - UCL Genetics Institute, University College London, London, United Kingdom
Marc J Williams - Memorial Sloan Kettering Cancer Center
Georgios Vlachogiannis - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Laura J Gay - Queen Mary University of London
Ann-Marie Baker - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Christopher Kimberley - Queen Mary University of London
Frederick J H Whiting - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Hayley L Belnoue-Davis - Department of Surgery and Cancer, Imperial College London, London, United Kingdom
Pierre Martinez - Université Claude Bernard Lyon 1
Maria Traki - Queen Mary University of London
Viola Walther - Queen Mary University of London
Kane Smith - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Javier Fernandez-Mateos - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Erika Yara-Romero - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Erica A Oliveira - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Salvatore Milite - Human Technopole
Giulio Caravagna - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Chela T James - Human Technopole
George Elia - Queen Mary University of London
Alison Berner - UCL Cancer Institute, UCL, London, United Kingdom
Chang-Ho Ryan Choi - St. George Hospital, Sydney, Australia
Pradeep Ramagiri - Tumour Profiling Unit (TPU), Institute of Cancer Research, London, United Kingdom
Ritika Chauhan - Tumour Profiling Unit (TPU), Institute of Cancer Research, London, United Kingdom
Nik Matthews - Tumour Profiling Unit (TPU), Institute of Cancer Research, London, United Kingdom
Jamie Murphy - Imperial College London
Anthony Antoniou - St. Mark's Hospital, London, United Kingdom
Susan K Clark - St. Mark's Hospital, London, United Kingdom
Miriam Mitchison - UCL Hospitals NHS Trust, London, United Kingdom
Jo-Anne Chin Aleong - Barts Health NHS Trust
Enric Domingo - University of Oxford
Inmaculada Spiteri - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Stuart A C McDonald - Queen Mary University of London
Darryl Shibata - Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California
Miangela M Laclé - University Medical Center Utrecht
Lai Mun Wang - University of Oxford
Morgan Moorghen - St. Mark's Hospital, London, United Kingdom
Ian P M Tomlinson - University of Edinburgh
Marco Novelli - UCL Hospitals NHS Trust, London, United Kingdom
Marnix Jansen - UCL Hospitals NHS Trust, London, United Kingdom
Alan Watson - Department of Gastroenterology, Barts Health, Whipps Cross Hospital, London, United Kingdom
Nicola Valeri - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Nicholas A Wright - Queen Mary University of London
John A Bridgewater - UCL Hospitals NHS Trust, London, United Kingdom
Manuel Rodriguez-Justo - UCL Hospitals NHS Trust, London, United Kingdom
Chris P Barnes - UCL Genetics Institute, University College London, London, United Kingdom
Hemant M Kocher - Centre for Tumour Biology, Barts Cancer Institute, London, United Kingdom
Simon J Leedham - University of Oxford
Andrea Sottoriva - Human Technopole
Trevor A Graham - Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
Publication Details: Cancer discovery, p.OF1
Publication Date: 21/01/2026
Grant note: A22909 / Cancer Research UK (CRUK) A19771 / Cancer Research UK (CRUK) 206314/Z/17/Z / Wellcome Trust (WT) A26815 / Cancer Research UK (CRUK) A22745 / Cancer Research UK (CRUK) 202778/Z/16/Z / Wellcome Trust (WT) National Institute for Health and Care Research (NIHR) 202778/B/16/Z, 105104/Z/14/Z / Wellcome Trust (WT) CA217376 / National Institutes of Health (NIH)
Identifiers: 991089523102346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer

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