AbstractIntroduction: Early diagnosis represents the best opportunity for cure of gastro-intestinal cancers; however current gastro-intestinal cancer screening programmes have low test sensitivity and low patient acceptability. It is hoped that a better understanding of carcinogenesis and the development of new biomarkers will provide answers to these clinical problems.
Hypothesis and aims: This thesis examines the current understanding of gastro-intestinal carcinogenesis focusing on colorectal and oesophageal cancers. It reviews the circulating gastro-intestinal cancer biomarker literature reporting the strengths, weaknesses and successes of current approaches.
The study tests the hypothesis that control patients and patients with colorectal and oesophageal neoplasia have differing plasma levels and fragmentation patterns of cell free nuclear and mitochondrial DNA, and that endoscopic removal of these lesions returns the levels and patterns to normal.
We aim to show how new techniques of DNA processing can improve results, and how the application of these results could form part of a diagnostic approach in an at risk population. We compare our results to and including carcinoembryonic antigen levels. Results: Cell free DNA was isolated from 164 patients, including 71 patients with oesophageal neoplasia, 50 patients with colorectal neoplasia, 35 patients without endoscopic abnormality and 8 patients with Barrett’s oesophagus.
This is the first report of statistically significant differences in circulating DNA quantities and patterns in patients with early oesophageal and colorectal neoplasia (p≤ 0.005). Logistic regression of the best DNA marker for colorectal neoplasia demonstrated a ROC of 0.888, with a sensitivity of 81.1% and specificity of 75.8%. Logistic regression of the best DNA marker for oesophageal neoplasia demonstrated a ROC of 0.778 with a sensitivity of 81.3% and specificity of 60.5%. Carcinoembryonic antigen performed poorly with a ROC of 0.547 and did not add diagnostically. There were no significant changes in markers from patients resected at endoscopy.
Conclusions: These circulating markers in combination with other markers offer the prospect of a simple blood test as a possible screen for colorectal and oesophageal dysplasia and cancers in an at risk population.
|Date of Award||Dec 2012|
|Supervisor||Alan Thorne (Supervisor), Pradeep Bhandari (Supervisor) & Ian A. Cree (Supervisor)|