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Title: Timing and importance of genomic instability in colorectal tumourigenesis, and association with clinico-pathological features
Author: Beggs, Andrew David
ISNI:       0000 0004 2723 9062
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2012
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Background Colorectal cancer is one of the most common cancer related causes of death in the UK. Several different pathways are known to be important in the initiation of colorectal cancer: chromosomal instability, microsatellite instability and CpG island methylation. It is unknown at what stage each of these facets becomes important, and their relative importance to each other. Aim To investigate the role and timing of genomic instability in the initiation of colorectal carcinogenesis, specifically it's role at the crypt, polyp and cancer level. Methods A variety of techniques were used to study DNA repair, microsatellite instability, methylation at the crypt level & whole genome methylation of tumours, DNA double strand break repair, tumour heterogeneity and the initiation of serrated adenomas via chromosomal instability. Results Through study of the different pathways of colorectal carcinogenesis a number of novel discoveries were made. It was found that microsatellite instability exists at a higher level than previously observed and is heterogeneously distributed in colorectal pre-malignant lesions, suggesting it's role may not be as clear-cut as previously supposed. Pre-malignant lesions were also found to be particularly heterogeneous for methylation of the DNA mismatch repair system, suggesting that this may play an important role. Study of whole genome methylation in carcinomas and adenomas as compared to normal colonic mucosa highlighted a number of pathways that may be relevant in colorectal cancer, as well as identification of a potential biomarker, GRASP. It was also found that the DNA double strand break (DSB) repair system has an important role in the progression of colorectal cancer, with tumours demonstrating faulty DSB repair having a worse prognosis. This study also demonstrated that tumour heterogeneity exists, with implications for treatment and prognosis. Finally, this study identified a gene potentially involved in the initiation of serrated adenomas, SLlT2. Conclusions This study has demonstrated the importance of genomic instability in colorectal cancer, identifying potential biomarkers and pathways involved in carcinogenesis. Further study is required based on these findings.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available