Burrell, RA; (2013) Replication Stress Links Structural and Numerical Chromosomal Instability in Colorectal Cancer. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Chromosomal instability (CIN), describing an increased rate of numerical and structural chromosome aberrations, is a principal driver of inter-cellular genetic heterogeneity in tumours. CIN is widely observed in solid malignancies, and is associated with poor patient outcome and drug resistance. Despite the prevalence and clinical impact of CIN in cancer, the underlying mechanisms still remain poorly characterised. Systematic characterisation of CIN+ colorectal cancer cells revealed that structurally abnormal chromosomes, generated through pre-mitotic defects, cause the majority of anaphase segregation errors. This contradicts a widely held hypothesis that CIN is caused by mitotic dysfunction. An investigation of the origins of these structural chromosome aberrations found that CIN+ cells display elevated DNA replication stress. Further experiments to investigate the link between replication stress and CIN demonstrated that induction of replication stress in diploid cells initiated both numerical and structural chromosomal instability. Through an integrative genomics approach, three novel putative CIN-suppressor genes (PIGN, RKHD2 and ZNF516) were identified, encoded on chromosome 18q, a genomic region subject to copy number loss in 80 per cent of CIN+ colorectal cancers. Silencing each of these three genes resulted in anaphase segregation errors and structural chromosome abnormalities. Cells depleted of the CIN-suppressors displayed evidence of DNA replication stress, phenocopying observations in CIN+ cells. Supplementing cells with exogenous nucleosides, which may alleviate replication stress, reduced both segregation errors induced by CIN-suppressor gene silencing, and endogenous segregation errors in cells with 18q loss. In summary, CIN in colorectal cancer appears to be driven through pre-mitotic generation of structurally abnormal chromosomes that are subsequently missegregated at anaphase, rather than through mitotic defects. These structurally abnormal chromosomes may result from elevated levels of DNA replication stress in CIN+ cells, which may be linked to the loss of three syntenic CIN-suppressor genes encoded on chromosome 18q.

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