Virus-induced cell-cell fusion as a driver of metastasis

Viral infection is thought to be responsible for 15% of all cancers and has previously been linked to cancer progression through the virus induced cell fusion theory of metastasis. This theory proposes that fusion of different cells may endow the result- ing hybrid cells with metastatic properties. I developed a number of measures that I applied to WGS data from 6,337 tumours to identify tumours in which cell fusion may have occurred. Based on these measures I identified 15 primary tumours, and 31 metastatic tumours with evidence of cell fusion, and further characterised their genomes. I also investigated cell fusion in vitro and generated a number of cell lines which underwent either virus induced cell fusion, or became tetraploid after a failure of cytokinesis, to study changes in karytoype and genome stability over time, and to elucidate whether differences could be observed resulting from the mechanism by which the genomes were duplicated. While the scope of this work was limited by experimental constraints, the conclusions were consistent with previous literature suggesting that whole genome duplication by any means results in an initial increase in heterogeneity, followed by adoption of a stable karyotype over time. Viral infection has also been associated with activation of several members of the Apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of cytidine deaminases that act on cytosines in single stranded DNA, in spe- cific cellular contexts including the developing immune system and as a response to invading viral pathogens. The action of these enzymes on DNA leaves specific, well defined, mutational signatures characterised by C to T and C to G transitions in particular contexts (single base substitution signatures known as SBS2 and SBS13, attributed to the activity of APOBEC3A and APOBEC3B). SBS2 and SBS13 mu- tations are observed in most cancer types, and have previously been associated with sites of chromosomal rearrangements. In this thesis I show that the presence and number of SBS2 and SBS13 mutations in the genome is associated with increasing genomic instability, and I introduce novel measures of genomic instability in whole genome sequencing (WGS) data. The relationship between viral infection, genomic instability, and APOBEC3 activity was also investigated but results remain inconclusive.