Dewhurst, SM; (2015) Whole genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Doctoral thesis , UCL (University College London).

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Abstract

Tetraploidy has long been proposed as an intermediate cellular stage en route to the aneuploidy and chromosomal instability that is observed in many cancer types. Although tetraploidy has been shown to be an unstable cellular state, an in depth analysis of the effect of a spontaneous tetraploidisation event on the cancer genome has not been carried out. Using an isogenic system of naturally occurring tetraploid cells derived from a chromosomally stable colorectal cancer cell line, the effect of tetraploidisation on genome stability over time was assessed. Tetraploid cells were shown to have increased structural and numerical instability on a per cell but not per chromosome basis. Over time the tetraploid genome became increasingly genomically unstable, which is likely due to the increased ability of tetraploid clones to propagate segregation errors. The genomic landscape of tetraploid clones began to recapitulate the genomic architecture of chromosomally unstable colorectal cancer, and allowed for the selection of clinically high risk chromosomal losses over time. Genome doubling was further shown to be a predictive marker of poor prognosis in colorectal cancer. Exhaustive analysis of DNA and mRNA failed to reveal any common changes in tetraploid clones that are likely to explain their aneuploidy tolerance phenotype. Instead a focussed siRNA screen of genes commonly mutated in genome-doubled tumours of multiple cancer types was carried out. Given the high-risk clinical phenotypes associated with tetraploidy and chromosomal instability, it remains a priority to identify the mechanisms allowing tumour cells to undergo tetraploidisation and to sustain chromosome segregation errors.

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