Sivakumar, Rangasamy (2017) Role of Cyclin D1 polymorphisms and protein over-expression in clinical outcomes of colorectal cancer. Masters thesis, Keele University.

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Abstract

Cyclin D1 is a key regulatory protein in the progression of G1-S phase of the cell cycle. Activated Cyclin D1 in turn activates S phase proteins and thereby leading to cell proliferation. Over expression of Cyclin D1 leads S phase cell cycle progression. There have been several individual studies that have tried to examine the pathways involved in Cyclin D1 protein expression and polymorphism in colorectal cancer and yet it lacks clarification. We examined the effects of CCND1 gene polymorphisms and their effect on clinical outcome on a cohort of about 634 sporadic colorectal cancer patients. We found that A/G870 polymorphism did not have any significant influence on clinical or survival outcomes. G/C1722 was associated with poor tumour grade (p=0.007, OR 2.17, 95% CI 1.23-3.83) and metastasis (p=0.022, OR 3.74, 95% CI 1.20-11.6). C/A1100 polymorphism was associated with left sided tumours (OR 3.66, P= 0.018, CI 1.25-10.76) and early stage disease (OR 0.40, p=0.012, CI 0.20-0.82). None of the polymorphisms significantly associated with Cyclin D1 over-expression. Over expression of Cyclin D1 protein was associated with early stage disease (OR 0.36, p=0.008, CI 0.17- 0.76), node negativity (OR 0.37, p=0.010, CI 0.17- 0.79) and improved survival (HR 0.54, p=0.006, CI 0.35-0.84). To investigate the mechanism underlying Cyclin D1 protein expression, we examined Cyclin D1 phosphorylation sites and found no mutations in these sites (n=27) (T286A, T156A). We then examined one of major pathways involved in regulation of Cyclin D1 expression in CRC namely β-catenin. Contrary to some studies, β-catenin expression was not significantly associated with Cyclin D1 over-expression. Cytoplasmic β catenin expression was significantly associated with poor clinical outcome and β-catenin gene mutations were rare in colorectal cancer. The samples with Cyclin D1 and β-catenin over-expression showed a significantly better 5-year survival (HR 0.43, p=0.019, CI 0.21- 0.87). From our study we infer that polymorphisms may not directly influence protein expression but were associated with tumour biology. The improved outcome observed with Cyclin D1 expression needs to be further elucidated. We also demonstrate that β catenin protein may not be only factor for Cyclin D1 protein expression in colorectal cancer in contrast to some other studies. We conclude that Cyclin D1 regulation remains a complex pathway involving both upstream and downstream genes.

Item Type: Thesis (Masters)
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Lisa Bailey
Date Deposited: 28 Apr 2022 15:25
Last Modified: 28 Apr 2022 15:25
URI: https://eprints.keele.ac.uk/id/eprint/10869

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