Tang, Joseph Man Fung (2010) Novel biomarkers for the diagnosis of pancreatic ductal adenocarcinoma: the proteomic approach. Masters thesis, University of Liverpool.
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Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of late presentation where the majority of patients present with non-specific symptoms and advanced disease. Current guidelines recommend that patients presenting with symptoms of suggestive of PDAC should be investigated by Contrast-Enhanced Computed Tomography (CE-CT). However, the radiographic features are often similar to benign diseases such as chronic pancreatitis (CP). Evidently, there is a need for a novel diagnostic biomarker, which can accurately identify patients with PDAC thereby reducing the number of otherwise unnecessary invasive procedures. Aim: The current thesis aimed to determine the potential of a number of serum proteins as diagnostic markers of PDAC. Method: Two approaches for the discovery and validation of diagnostic markers of PDAC were employed. In Chapter 2, the serum expression of three iTRAQ- Mass Spectrometry identified proteins (vitamin d-binding protein [VDBP], retinol-binding protein 4 [RBP-4], and fibronectin [FINC]) were validated by western blotting in a three-phased study consisting of 20, 60, and 120 serum samples. Their diagnostic potentials as individual and combined markers were assessed statistically. In Chapter 3, the serum concentrations of 27 cytokines, chemokines, and growth factors (CCGFs) in 90 PDAC and 90 controls were quantified using the multiplex cytokines assay and the potential of individual CCGFs for the diagnosis of PDACs were assessed. One-hundred and twenty serum samples were randomly allocated to discovery where stepwise regression was used to select independent CCGF markers of PDAC. These were then combined into a single marker and the diagnostic accuracy for PDAC assessed. Finally, validation utilised the remaining sixty samples to investigate the accuracy of the combined CCGF marker for the diagnosis of PDAC. Results: Results from Chapter 2 showed that the serum concentrations of VDBP, RBP-4, and FINC were significant decreased in PDAC with ROC-AUCs of >0.74 against CP and healthy volunteers (HC). However, their diagnostic accuracies were decreased (ROC-AUC <0.63) in the presence of individuals with biliary obstruction (disease controls, DC). Combining all three markers increase the diagnostic accuracy for PDAC against HC and CP (ROC-AUC, 0.91) but not against DC (ROC-AUC, 0.74). Further validation using pre-diagnostic serum samples showed that a small subset of patients exhibited a gradual decline in the serum concentration of VDBP and RBP-4 closer to diagnosis. Results from Chapter 3 showed that fourteen CCGFs were differentially expressed in PDAC compared to controls, of which, IFN-gwas the most significant individual marker of PDAC with comparable accuracy to CA19-9. Discovery analysis identified four independent markers of PDAC. When combined, an ROC-AUC of 0.99 was achieved. Validation of the combined CCGF marker in yielded encouraging results of ROC-AUC >0.95. Conclusion: A combined marker consisting of four selected CCGFs may serve as a potential diagnostic marker for pancreatic cancer and its use in the clinical setting may improve the current diagnostic process.
|Item Type:||Thesis (Masters)|
|Subjects:||R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)|
|Departments, Research Centres and Related Units:||Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Cancer Studies|
|Deposited On:||06 Jan 2012 09:48|
|Last Modified:||07 Jan 2012 01:00|
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