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Title: Identification and characterisation of novel protein biomarkers for colorectal cancer prognosis
Author: Alnabulsi, Abdo
ISNI:       0000 0004 7425 7968
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2018
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Colorectal cancer is a common malignancy and a leading cause of cancer-related deaths. Despite the undisputable value of staging systems, there is a need to identify biomarkers for colorectal cancer prognosis. The abnormal expression of brown fat-like phenotype has been implicated in tumour development and growth. Therefore, the expression of these proteins in tumour cells could be associated with colorectal tumour prognosis. Monoclonal antibodies to brown fat-associated proteins CIDEA, ELOVL3, ELOVL5, ELOVL7, UCP1, SLA2 and WSB1 were developed using the short peptide approach (PRDM16 was commercially outsourced). To generate each antibody, a unique immunogen peptide was identified for each target using a combination of bioinformatics and antigenicity prediction models. The antibodies were then used to profile the expression of protein targets by immunohistochemistry on a tissue microarray comprising of 823 primary colorectal cancers and 50 normal colonic mucosa samples. The prognostic significance of each protein was then assessed by univariate and multivariate survival analyses. Each antibody showed immunoreactivity in normal colonic epithelium and primary tumour, except UCP1 which showed immunoreactivity only in tumour samples. The expression of CIDEA (p<0.001) and ELOVL5 (p<0.001), ELOVL7 (p=0.015), cytoplasmic PRDM16 (p<0.001), UCP1 (p<0.001) and SLA2 (p<0.001) were significantly higher in primary tumour compared to normal colonic mucosa. Whereas, the expression of ELOVL3 (p=0.043) and nuclear PRDM16 (p<0.001) were significantly lower in primary tumour tissue. Immunoreactivity for UCP1 (p<0.001) and CIDEA (p=0.004) was significantly associated with better survival. High ELOVL5 expressing tumours (p=0.006) and strong ELOVL3 expressing tumours (p=0.022) were also associated with better prognosis. The expression of UCP1 emerged as the best prognostic target as it showed strong and consistent associations with survival in different cohorts and using different cut-off points. Furthermore, UCP1 was independently prognostic in a range of multivariate models which included established prognostic parameters. To conclude, novel and promising pathway associated with tumour progression have been identified in colorectal cancer. Furthermore, UCP1 is a potential prognostic biomarker, which could also be valid target for therapeutic interventions.
Supervisor: Murray, Graeme ; Cash, Beatriz Gimenez Sponsor: Vertebrate Antibodies Limited (Aberdeen ; UK)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemical markers ; Monoclonal antibodies ; Colon (Anatomy) ; Rectum