Mechanisms Driving Chromosomal Instability and Cancer Genome Evolution

Comprehensive genomic analyses of cancers have provided important insights into tumour evolution and revealed that tumours are frequently heterogeneous entities composed of multiple genetically and phenotypically distinct subclones. Intratumour heterogeneity confounds clinical decision-making, and contributes to the emergence of drug resistant tumour subclones. An important source of genetic heterogeneity in tumours is genomic instability, which is observed in a large proportion of tumours. It is therefore important to understand instability mechanisms and their associated genomic lesions. Our work has highlighted the importance of replication stress as a driver of chromosomal instability. Chromosomally unstable cancer cells display structural chromosome aberrations that lead to missegregation during cell division, thereby contributing to both numerical and structural karyotypic heterogeneity. We also identified three novel suppressors of replication stress and chromosomal instability encoded on chromosome 18q, which is recurrently lost in chromosomally unstable colorectal cancer. We are also examining the role of whole genome-doubling in the tolerance of aneuploidy and chromosomal instability, as well as its role in the rapid evolution of the unstable cancer genome. Underscoring the importance of mechanisms generating heterogeneity in disease progression, a genome-doubling event was independently predictive of poorer relapse free survival in early stage colorectal cancers in two independent patient cohorts. Disclosure: The author has declared no conflicts of interest.