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An investigation of the prognostic value of pathological and genomic factors in pancreatic ductal adenocarcinoma

Jamieson, Nigel Balfour (2012) An investigation of the prognostic value of pathological and genomic factors in pancreatic ductal adenocarcinoma. PhD thesis, University of Glasgow.

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Abstract

Improving the survival of patients with pancreatic ductal adenocarcinoma (PDAC) remains an oncological and surgical challenge. PDAC pathogenesis is underlined by numerous molecular aberrations occurring at a genetic and epigenetic level, however their spectrum of occurrence and clinical impact has not yet been fully elucidated. The majority of patients present with locally advanced or metastatic disease and even the 15-20% of patients who undergo resection for cure have a median survival limited to 18-24 months. Surgical treatment carries a high morbidity and identification of patients expected to have a poor prognosis could assist in the decision making process. The present thesis examines the prognostic importance of pathological and molecular factors in PDAC, specifically: 1. An examination of the frequency, the prognostic impact of resection margin involvement, and furthermore the prognostic influence of tumour involvement at individual margins. 2. Determination of the prognostic impact of peripancreatic fat invasion following resection of PDAC. 3. The investigation of the relationship of candidate protein biomarker expression with overall survival in a large PDAC tissue microarray cohort using immunohistochemistry. 4. Determining gene expression profiles associated with pancreatic cancer compared to normal tissue using gene expression microarray analysis with subsequent development and validation of a prognostic gene signature. 5. microRNAs were identified that associated with pancreatic cancer clinicopathological factors including survival. 6. Copy number aberrations were identified using array comparative genomic hybridisation that correlated with clinicopathological factors following resection for PDAC. 7. Finally the identification of potentially important regulator genes contributing to pancreatic tumourigenesis, was made by integrating the gene expression, microRNA expression and copy number data from previous sections using a bioinformatic approach. In this work a combination of enhanced pathological staging criteria along with the correlation of molecular marker expression and genomic profiling signatures with clinical outcome data has yielded interesting results in patients undergoing resection for pancreatic cancer that allowed detailed disease characterisation and subsequent clinically relevant outcome stratification.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Pancreatic cancer, Surgery, Prognosis, Pancreaticoduodenectomy, Resection margin, Prognostic biomarkers, Gene expression signature, MicroRNAs, ArrayCGH, Bioinformatics
Subjects: R Medicine > RB Pathology
R Medicine > RD Surgery
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Supervisor's Name: Oien, Dr. Karin A. and McKay, Mr. Colin J.
Date of Award: 2012
Embargo Date: 18 October 2015
Depositing User: Mr Nigel Balfour Jamieson
Unique ID: glathesis:2012-3677
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Oct 2012
Last Modified: 10 Dec 2012 14:09
URI: http://theses.gla.ac.uk/id/eprint/3677

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