Evolution of karyotype landscapes in cancer

Chromosomal instability (CIN) is a phenomenon where cells mis-segregate chromosomes more frequently than normal. As a result of CIN, cells can gain and lose whole chromosome and acquire an aneuploid karyotype. Despite their association with detrimental cell growth, both aneuploidy and CIN are commonly observed in proliferating cancer cells. It is suggested that CIN provides adaptive capacity to cells by enabling rapid emergence of genomic alterations that enhance tumorigenesis or metastatic potential. CIN has been shown to contribute to intra-tumour heterogeneity, metastasis, and therapy resistance. However, a better understanding of the dynamics of karyotype evolution is still needed to understand how CIN drives tumour progression. Most existing methods used to map tumour karyotypes cannot fully dissect intra-tumour karyotype heterogeneity. The overall aim of this thesis is to better understand karyotype evolution in tumour cells that undergo continuous CIN using single-cell sequencing and state-of-the-art mouse models. A new bioinformatics method, Aneufinder, was developed to determine single-cell karyotypes in CIN-driven tumour cells. Using single-cell sequencing and Aneufinder in mouse models for T-cell lymphoma, we show that tumours quickly select for recurrent karyotype aberrations to promote tumour growth. These findings were supported using an in silico model and further investigated in various human cancers, including B-cell leukaemia, basal cell carcinoma, and paediatric cancers. Together these data underline a role for CIN driving tumour heterogeneity and adaptivity, that can be used to further understand tumour progression and thus help improve clinical prognosis