High-grade serous ovarian carcinoma (HGSOC) is characterised by genomic instability, ubiquitous TP53 loss, widespread disease at diagnosis and the frequent emergence of platinum resistance. This thesis explores the use of high-throughput genomics technologies to understand if resistance could be explained by the model of tumour evolution. We performed SNP array analysis of a cell line model system of platinum resistance consisting of matched cell lines from three cases of HGSOC established before and after clinical resistance developed, the OVOl clinical study consisting of six matched pairs of tumours before and after three cycles of chemotherapy, and the OV03/0V04 study consisting of 18 cases sampled at multiple timepoints and from multiple metastatic sites. The results showed evidence of metastatic site dependent divergence. Moreover, mutually exclusive loss of heterozygosity patterns between presentation and relapse genomes, including all the cases in the cell line system and one of two OV03 cases for which relapse material was available, suggest that the relapse arises from a minor subclone of the presentation disease, while in the remaining case, the subclone with an NFJ homozygous deletion was enriched in the relapsed disease. I then asked which mutational process drives evolution. Using next-generation sequencing (NGS), I compared the structural variants between and within cases in the model system and in 6 cases of the OV03 cohort. From the genomic signatures in the cell lines, I demonstrated that a case with homologous recombination (HR) deficiency acquired numerous translocations and small deletions (median size of 13.4kb) , whereas another showed a novel tandem duplicator phenotype (median size of tandem duplications was 350kb). Mutator phenotypes in both cases arose early in progression and persisted, but the tumour with HR deficiency showed evidence of re-stabilising its ,"genome and lost platinum sensitivity after a revertant BRCA2 mutation restored its HR function. A subset of tumours from the Cancer Genome Atlas (TCGA) dataset suggested that these two phenotypes were mutually exclusive. Amongst the six OV03 cases, preliminary analysis suggests that one case showed an amplifier phenotype and three cases showed evidence of parallel evolution. Taken together, early onset of mutator phenotypes and parallel evolution may provide a mechanism by which resistance evolves. Further work should aim to identify the processes involved in tumour evolution in 'purified' populations such as cancer stem cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:610159 |
| Date | January 2012 |
| Creators | Ng, Kiu Yan Charlotte |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/265590 |
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