TY - JOUR T1 - Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer JF - bioRxiv DO - 10.1101/2020.03.26.007138 SP - 2020.03.26.007138 AU - William Cross AU - Maximilian Mossner AU - Salpie Nowinski AU - George Cresswell AU - Abhirup Banerjee AU - Marc Williams AU - Laura Gay AU - Ann-Marie Baker AU - Christopher Kimberley AU - Hayley Davis AU - Pierre Martinez AU - Maria Traki AU - Viola Walther AU - Kane Smith AU - Giulio Caravagna AU - Sasikumar Amarasingam AU - George Elia AU - Alison Berner AU - Ryan Changho Choi AU - Pradeep Ramagiri AU - Ritika Chauhan AU - Nik Matthews AU - Jamie Murphy AU - Anthony Antoniou AU - Susan Clark AU - Jo-Anne Chin Aleong AU - Enric Domingo AU - Inmaculada Spiteri AU - Stuart AC McDonald AU - Darryl Shibata AU - Miangela M Lacle AU - Lai Mun Wang AU - Morgan Moorghen AU - Ian PM Tomlinson AU - Marco Novelli AU - Marnix Jansen AU - Alan Watson AU - Nicholas A Wright AU - John Bridgewater AU - Manuel Rodriguez-Justo AU - Hemant Kocher AU - Simon J Leedham AU - Andrea Sottoriva AU - Trevor A Graham Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/28/2020.03.26.007138.abstract N2 - Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection. ER -