Chambers, W.; (2011) Dukes stage B colorectal cancers analysed with array comparative genomic hybridisation. Doctoral thesis , UCL (University College London).

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Abstract

Introduction: The main aim was to investigate Dukes B cancer prognosis using array comparative genomic hybridisation (aCGH). The cancers were typed for microsatellite instability (MSI), APC loss of heterozygosity (LOH) and ploidy. A secondary aim was the selection, on the basis of aCGH results, of potential colorectal cancer genes using In Situ Hybridisation (ISH). Sporadic adenomas were also investigated with aCGH to investigate the timing of chromosomal instability in tumourigenesis. Methods: Dukes B cancers collected in Oxford, Leeds and Harrow were examined using aCGH based on a set of 3452 BAC clones at ~1Mb spacing. MSI was assessed using BAT26 and D5S346. D5S346 gave LOH at the APC gene locus. Ploidy was assessed using flow cytometry (FACS). From the aCGH data genes in regions of copy number gain were chosen for ISH analysis. Results: 79 Dukes B cancers (43 good outcome, 36 bad outcome on the basis of 5 year survival) were investigated with aCGH. The most commonly gained chromosomes across all cancers were 13, 20 and 7, and the most commonly lost were 22, 18 and 14. Comparing survival groups; chromosome 6 was more often lost in cancers associated with good outcome, chromosome 16 was more often gained in microsatellite stable cancers associated with good outcome, and chromosome 22 more often gained in microsatellite stable cancers associated with poor outcome. Chromosome 13 showed greater than single copy number change significantly more often in bad outcome cancers. Several new areas of small genomic gain and loss were detected. Four candidate genes were identified (CDX2, RHOA, FLT1 and ARHGEF1). None showed a relationship with outcome. Large scale chromosomal changes were found in 10 of14 sporadic adenomas. Conclusions: Array CGH did identify some difference between good and bad outcome Dukes B cancers. However on the basis of this data, the technique could not be used as a useful clinical tool to predict prognosis.

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