Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer
Year: 2026
Type: article
Study design: Observational Study
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. SIGNIFICANCE: 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. See related commentary by Okada et al., p. 192.
Source: Cancer Discovery
Authors: 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
Institutions: University of Reading, Institute of Cancer Research, Queen Mary University of London, Barts Cancer Institute, St. Anna Children's Cancer Research Institute, University College London, Memorial Sloan Kettering Cancer Center, Imperial College London, Lyon 1 Université, Centre National de la Recherche Scientifique, Inserm, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Human Technopole, St George Hospital, St Mark's Hospital, Barts Health NHS Trust, Royal London Hospital, University of Oxford, University of Southern California, University Medical Center Utrecht, Centre for Human Genetics, Western General Hospital, Edinburgh Cancer Research, Institute of Genetics and Cancer, University of Edinburgh, Whipps Cross University Hospital
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7125192804