An Analysis of the Role of Polymorphisms Within the TNF Locus and the Development and Progression of Colorectal Adenocarcinoma

Campbell, David Andrew (1995) An Analysis of the Role of Polymorphisms Within the TNF Locus and the Development and Progression of Colorectal Adenocarcinoma. PhD thesis, University of Glasgow.

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Colorectal cancer represents the second most common form of malignancy in the Western World and with over 20,000 deaths in the UK each year this disease represents a major health problem. The genetic component of this malignant disease has received much attention over the past few decades and it is now becoming clear that development of colorectal cancer is a muti-stage process and that a number of genes are involved at various stages of the process. Central to any malignant disease is the question of why the immune system allows a tumour to grow given that under the correct conditions the host immune system is capable of mounting an immune response. Central to the modulation of the immune response is a family of cytokines termed the tumour necrosis factors (TNFalpha, Lymphotoxin-alpha (LTalpha) and LTbeta). Low levels of TNFalpha have been shown in colorectal tumours and it has been suggested that the constant exposure of tumour cells to low levels of TNFalpha may result in the cells becoming desensitised to the cytotoxic activity TNFalpha. Why such low levels of TNFalpha production should occur are however unclear. Recently a number of polymorphisms have been identified within the region of the TNF genes and a number of studies have demonstrated a link between specific alleles of these polymorphisms and a number of autoimmune and non-autoimmune diseases and a possible genetic predisposition to either over- or under-production of TNFalpha. The genotypes at six of the TNF polymorphism (TNFa, TNFc, TNFd, TNFe, -308 TNFalpha, LTalpha Ncol) loci of 100 individuals with clinically defined colorectal cancer were compared to those of 115 normal non-malignant control individuals. The data presented in this thesis clearly identifies that alleles of the TNF polymorphisms are markers of not only the presence of colorectal cancer but also the aggressiveness of the disease. In particular alleles of the TNFalpha, TNFd and TNFe microsatellites seem to be associated with the presence (TNFa3 and all; TNFd3; TNFe3) or absence (TNFal, a5, a9 and a 13; TNFe2) of colorectal cancer whilst an extended genotype involving the LTalpha Ncol RFLP and the -308 TNFalpha RFLP may also be involved. Similar data is observed in a small study of 23 gastric adenocarcinoma patients. An examination of the relationship between these polymorphisms and Dukes' staging also suggests that these markers may be involved in the aggressiveness of this malignant disease with alleles of both the RFLPs and the microsatellites showing associations with different Dukes' stages, whilst an association is also shown with the presence or absence of secondary disease. It is still unclear whether these polymorphisms are functional or whether they represent markers for a near-by gene which is involved in the process of colorectal tumourigenesis. The possible reasons for these associations are discussed and future strategies for determining the role of these polymorphic markers in the carcinogenesis of colorectal cancer are suggested.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Grant Gallagher
Keywords: Oncology
Date of Award: 1995
Depositing User: Enlighten Team
Unique ID: glathesis:1995-76312
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 15:47
Last Modified: 19 Nov 2019 15:47

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