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Title: Chromosomal imbalances in colorectal cancer
Author: Davison, Eleanor Jane
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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A genomic microarray with a genome wide resolution of ~1Mb was constructed, consisting of approximately 3500 large insert clones selected from the “golden path” sequencing clone set. Also included on the array were clones chosen to represent 142 cancer-associated genes and a human chromosome specific subtelomeric clone set. The 1Mb array was validated and used to investigate genomic copy number changes in 48 colorectal cancer cell lines and 37 primary colorectal cancers. The samples were divided for analysis according to type of genomic instability; microsatellite (MSI) or chromosomal (CIN). Consistent copy number changes were identified, including gain of chromosomes 20, 13 and 8q and smaller regions of amplification such as chromosome 17q11.2-q12. Loss of chromosome 18q was a recurrent finding, along with deletion of discrete regions such as chromosomes 20p12.1-p11.23 and 4q34-q35. A greater number of aberrations were detected in CIN+ than MSI+ samples, as well as differences in the particular changes reported. Expression analysis using Affymetrix whole genome oligonucleotide arrays was carried out on ten of the colorectal cancer lines and changes in expression of genes located in the recurrent regions of gain and loss were identified. The deletion of chromosome 20p12.1-p11.23 was analysed at higher resolution using a specifically designed array with tiling path coverage of the region; a recurrent homozygous deletion was identified and the minimum region of loss refined to ~200Kb. Two non-coding RNA genes which map to this region, bA318C17.1 and dJ974N19.1, were investigated using mutation analysis and quantitative PCR. Sequence changes in bA318C17.1 and reduced expression of both genes were detected in colorectal cancer cell lines. A number of genes of interest have been identified, displaying altered expression and located within the common regions of copy number change, which are likely to be of importance in the development of colorectal cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available