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Title: The role of DNA methylation in the progression of colorectal neoplasia
Author: Ibrahim, A. E. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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I optimized a microarray method for identifying genome-wide CpG island methylation changes called Microarray-based Methylation Assessment of Single Samples (MMASS). A prospective sample set of matched normal colorectal mucosa, adenoma and adenocarcinoma tissues were collected as well as a retrospective set of primary colorectal carcinomas and where present their metastatic tissues. All cases were assayed for microsatellite instability. Genome-wide methylation patterns were profiled using MMASS and were correlated with their corresponding genome-wide expression changes for a subset of the cases. Differentially methylated and expressed targets were identified during neoplastic progression of CRC. DNA methylation was measured in a set of 10 CpG islands known to be important in CRC, using quantitative pyrosequencing assays, in 261 tissue samples from 138 colectomy specimens removed for CRC and 9 for diverticular disease. Recursive partitioning (RP) was used to identify threshold methylation levels that discriminated normal tissue from neoplastic tissues with 100% sensitivity (95% CI: 93.2-100.0) and 90.5% specificity (95% CI: 69.6-98.8). DNA methyltransferase DNMT3B has been implicated in the progression of colorectal neoplasia. Immunohistochemical analysis of the expression of DNMT3B was positively correlated with methylation of SFRP2 (r = 0.415, p ≤ 0.001) and negatively correlated with methylation of IGF2 DMR0 (r = -0.262, p = 0.014). SFRP2 and IGF2 CpG islands methylation changes are proposed to be potential biomarkers for CRC screening. Faecal DNA can be tested for methylation levels of SFRP2adn IGF2 to identify high risk patients. The UK NHS bowel cancer screening programme is the ideal environment in which to take these findings forward.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available