Abstract PR06: Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, and has clinical relevance as a prognostic marker and potential therapeutic target. We have previously shown that in colorectal cancer (CRC), aneusomies largely occur upon the transition from benign adenoma to invasive carcinoma (Cross et al., 2018), however the temporal evolutionary dynamics that select for aneuploidy throughout CRC progression remain broadly uncharacterised. We performed multi-region genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of CRC progression, and longitudinally tracked 22 individual CRC tumours through metastasis and treatment. Genetic diversity measures revealed that although adenomas exhibited low levels of aneuploidy (8.5% genome altered), they harboured high intra-tumour heterogeneity (ITH), whereas cancers had significantly higher aneuploidy (27.2% genome altered) but proportionally lower ITH (p=0.0017), indicating that progression to malignancy is through a genetic bottleneck that suppresses diversity. We generated genome-wide copy number profiles from individual CRC glands, and showed that glands from the same tumour had similar karyotypes, yet displayed ongoing instability at the single cell level. Remarkably, we found that aneuploid genomes were broadly stable in metastatic lesions, even after chemo- or targeted therapies, and in recurrences detected many years after the primary diagnosis. Computational modelling of the dynamics of aneusomy accrual during CRC progression to metastasis was consistent with stabilising selection acting to ‘trap’ cancer cell genomes on a fitness peak defined by the optimal patterns of aneuploidy. These data show that although a genetic bottleneck underlies the initial progression from adenoma to CRC, further evolution of CRC is constrained largely by stabilising selection, even through metastatic dissemination and therapeutic resistance. References Cross, W., Kovac, M., Mustonen, V., Temko, D., Davis, H., Baker, A.-M., … Tomlinson, I. P. M. (2018). The evolutionary landscape of colorectal tumorigenesis. Nature Ecology & Evolution, 2(10), 1661–1672. https://doi.org/10.1038/s41559-018-0642-z Citation Format: Salpie Nowinski, William Cross, Maximilian Mossner, George Cresswell, Abhirup Banerjee, Marc Williams, Laura Gay, Ann-Marie Baker, Binxgin Lu, Christopher Kimberle