Colorectal carcinoma arises through sequential genetic changes whereby an adenoma develops from normal colonic epithelium and then becomes a carcinoma. Critical to this process is two forms of mutually exclusive genomic instability ?? chromosomal instability (CIN) and microsatellite instability (MSI). The colorectal tumours that develop from each of these pathways have distinct pathological and molecular differences. Most MSI+ colorectal carcinomas are associated with the CpG island methylator phenotype (CIMP) - an epigenetic phenomenon where a specific and consistent group of genes are silenced through promoter methylation. However, over half of fall CIMP+ colorectal tumours are microsatellite stable (MSS). It is well known that the WNT/β-catenin signalling pathway is instrumental in the initiation and development of CIN type tumours but it is less clear whether this pathway has any significant involvement in MSI+ or methylated tumours. The role of the PI3K1AKT signalling pathway in the development of solid human tumours has only recently been established and the affects of abnormal PI3K/AKT signalling in sporadic colorectal carcinomas is yet to be fully elucidated. The objective of this thesis was to investigate the involvement of the WNT/β-catenin and PI3K/AKT signalling pathways in the CIN, MSI+ and methylated subgroups of sporadic colorectal carcinoma. To achieve this, the expression patterns of β-catenin, p-AKT and PTEN were identified by immunohistochemistry on sections from tissue microarrays consisting of cores from a large group of sporadic colorectal carcinomas. Each of these proteins is an integral part of the constitutive activation of WNT/β-catenin or PI3K/AKT signalling and their expression patterns were correlated with the clinical, pathological and molecular characteristics of the different subgroups of colorectal carcinoma. Increased nuclear β-catenin expression, an indicator of activated WNT signalling, is associated with MSS and the pathological features of CIN type tumours and inversely associated with the pathological and molecular features of MSI+ and CIMP+ tumours. In all forms of sporadic colorectal carcinoma, nuclear β-catenin expression was not an indicator of overall survival. PTEN was not associated with any particular subgroup of sporadic colorectal carcinoma, but decreased cytoplasmic expression was indicative of overall worse outcome, especially in MSS or CIN type tumours. While the identification of nuclear β-catenin in sporadic colorectal carcinomas is not a satisfactory prognostic marker, the immunohistochemical detection of absent PTEN expression may prove useful in identifying poor outcome in individuals with sporadic MSS colorectal carcinoma.
| Identifer | oai:union.ndltd.org:ADTP/258629 |
| Date | January 2008 |
| Creators | Mckenzie, Gavin, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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