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Title: The Influence of Microsatellite Instability on Survival in Colorectal Cancer.
Author: Phillips, Simon M.
ISNI:       0000 0001 3489 4581
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2005
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Colorectal cancers that express Micro~atellite Instability (MSI) differ in many clinicopathological and genetic features from 'sporadic' tumours. They also appear to confer an improved prognosis, roughly translating into a 10-20% improvement in S-year patient survival. This advantage is independent of patient age or tumour stage, despite these tumours co~only displaying otherwise advers~- features' such as poor tumour differentiation or mucinous tumour characteristics. One common explanation is that the 'mutator phenotype' limits tumour aggressiveness, but in fact MSI+ colonic adenomata progress faster towards invasive malignancy. Alternatively these tumours may invoke an enhanced immunological response, directed against tumour-derived antigens, which in turn affects the aggressiveness of MSI+ tumours. Although many workers have shown a quantitative increase in tumour lymphocytes compared with MSI- tumours, direct evidence showing that MSI+ tumours elicit enhanced cytotoxicity is limited. Moreover it implies only indirectly that lymphocytes within MSI+ tumours are activated in an antigen-specific manner. In a consecutive series of over 200 prospectively analysed colorectal cancers we assessed populations ofCD8+ and CD4+ T-cells, relative levels 0 f lymphocyte cytotoxicity (Granzyme B), and the degree ofantigen-specific activation in the tumour lymphocyte populations (Interleukin 2 receptor ex-subunit). Complimentary techniques were used. Firstly, gene expression of all markers was determined by real-time fully quantitative RT-PCR (faqman) to assay mRNA levels within fresh-frozen tumour samples. Secondly, protein expression of markers was compared using appropriate monoclonal antibodies and immunohistochemistry (IHC) from formalin-fixed paraffin-embedded specimens. Microsatellite stable (MSI-) and MSH groups were directly compared. In addition, clinico-pathological data was correlated with immunological variables in order to identify Supplied by The British Library - 'The world's knowledge' any independently predictive features for eitllCr survival, or for use as a model to allow identification of MSI+ tumours by incorporating standard c1inico-pathological variables and simple immunohistochemistry. The findings of this work corroborate the commonly reported c1inico-pathological features of MSI+ tumours. In addition we demonstrate significant differences in T-cell mRNA expression and immunohistochemical quantity, bOtll overall (CD3+) and for CD8+ and CD4+ subsets. Moreover, an observed significant difference in Granzyme B levels and IL2-RiX expression suggests tllat the lymphocyte population in MSI+ tumours is botll more highly activated and tllat this activation is likely to be antigen-specific. No firm commentary on survival differences can be made witllin our study group, nor prognostic relationships to any measured variable. Comparisons between the mRNA expression data and immunohistochemistry are made and tlle limitations of each technique are discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available