Key Points
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Chromosomal instability (CIN) drives intratumoural heterogeneity, resulting in the temporal and spatial diversification of tumour subclones
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CIN enables cancer cells to rapidly explore complex genetic makeups by potentially causing the simultaneous acquisition of whole-chromosome or segmental aneuploidy, structural chromosomal aberrations, and the acquisition of mutations
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CIN accelerates phenotypic adaptation under selective pressures encountered during tumour evolution and therapy, leading to a poor clinical outcome
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Paradoxically, high levels of CIN are tumour suppressive owing to the frequent generation of unviable karyotypes, while CIN tolerance and attenuation mechanisms allow an optimal equilibrium to be reached, leading to sustainable CIN propagation
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A deeper understanding of the vulnerabilities associated with CIN and the development of clinically applicable biomarkers are needed both for patient stratification and to leverage new therapeutic opportunities
Abstract
Aberrant chromosomal architecture, ranging from small insertions or deletions to large chromosomal alterations, is one of the most common characteristics of cancer genomes. Chromosomal instability (CIN) underpins much of the intratumoural heterogeneity observed in cancers and drives phenotypic adaptation during tumour evolution. Thus, an urgent need exists to increase our efforts to target CIN as if it were a molecular entity. Indeed, CIN accelerates the development of anticancer drug resistance, often leading to treatment failure and disease recurrence, which limit the effectiveness of most current therapies. Identifying novel strategies to modulate CIN and to exploit the fitness cost associated with aneuploidy in cancer is, therefore, of paramount importance for the successful treatment of cancer. Modern sequencing and analytical methods greatly facilitate the identification and cataloguing of somatic copy-number alterations and offer new possibilities to better exploit the dynamic process of CIN. In this Review, we describe the principles governing CIN propagation in cancer and how CIN might influence sensitivity to immune-checkpoint inhibition, and survey the vulnerabilities associated with CIN that offer potential therapeutic opportunities.
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Acknowledgements
B.V. gratefully acknowledges financial support from Cancer Research UK (CRUK; C23338/A15965) and the UK National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. C.S. gratefully acknowledges financial support from the Breast Cancer Research Foundation (BCRF), CRUK (TRACERx), the CRUK Lung Cancer Centre of Excellence, the CRUK University College London Experimental Cancer Medicine Centre, the European Research Council (THESEUS) and the Marie Curie Network and European Commission PloidyNet, the Francis Crick Institute (which receives its core funding from CRUK (FC001169), the Novo Nordisk Foundation (ID 16584), the Prostate Cancer Foundation, the Rosetrees Trust, Stand Up 2 Cancer (SU2C), the UK Medical Research Council (FC001169), the Wellcome Trust (FC001169)), and the UK NIHR, and the University College London Hospitals Biomedical Research Centre.
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L.S. became a full-time employee of Novartis after submission of this manuscript. B.V. has acted as a consultant of Karus Therapeutics. In the past 36 months, C.S. has acted as a consultant and speaker for Boehringer Ingelheim, Novartis, and Roche, has acted as a speaker for Celgene, Eli Lilly, GlaxoSmithKline, Pfizer, and Servier, serves as an advisory board member for and retains stock options in ApoGen Biotechnologies, Epic Sciences, and GRAIL, has served as an advisory board member and receives honoraria from Natera, and is the founder of, and retains stock options in, Achilles Therapeutics.
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Sansregret, L., Vanhaesebroeck, B. & Swanton, C. Determinants and clinical implications of chromosomal instability in cancer. Nat Rev Clin Oncol 15, 139–150 (2018). https://doi.org/10.1038/nrclinonc.2017.198
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DOI: https://doi.org/10.1038/nrclinonc.2017.198
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