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Title: Metabonomic profiling of oesophageal cancer
Author: Yakoub, Danny
ISNI:       0000 0004 2681 9399
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Background and aims Early detection of oesophageal cancer is the most effective strategy to improve its outcome. The thesis explores the metabolic characteristics of oesophageal tumours as compared to normal tissue from same patients as well as that from healthy individuals. The aim is to characterise the basic metabolic profile of oesophageal cancer, detect possible evidence of field cancerization and to characterise effect of chemotherapy on oesophageal cancer tissue. The clinical benefit is to develop a non-invasive early test to be translated to the bed side/laboratory practice for screening, diagnosis and prediction of response to chemotherapy for patients with oesophageal tumours. Methods Using 1H Magic Angle Spinning – Nuclear Magnetic Resonance (MAS-NMR) spectroscopy of intact tissue, we generated metabolic profiles of tumour tissue, proximal histologically normal mucosa from cancer patients (PHINOM) and mucosa from a control group. Using multivariate regression and receiver-operator characteristic analysis we were able to identify a panel of metabolites discriminating malignant and histologically-normal tissues from cancer patients from that of controls. Results While 26% and 12% of the spectral profile regions were uniquely discriminating tumour or control tissue respectively, 5% of the profile exhibited a significant progressive change in signal intensity from controls to PHINOM to tumour. Regions identified were assigned to phosphocholine, glutamate, myo-inositol, adenosine-containing compounds, uridine4 containing compounds and inosine. In particular, the phosphocholine to glutamate metabolite ratio in histologically-normal tissue signified the presence of oesophageal cancer (n=123, AUC 0.84, p<0.001). Metabolites that were found to be significantly altered in correlation to response to chemotherapy are lysine, glutathione, creatine, taurine, uracil and tyrosine Conclusion The results of the study enable better understanding of the metabolic perturbations in oesophageal and cancer. The findings support the hypothesis that field effects are present in oesophageal cancer, even in the absence of Barrett’s oesophagus. This indicates that metabolic profiling of tissue can potentially play a role in the surveillance of cancer especially in high risk groups. It also shows the potential of using this methodology to study the prediction of response to chemotherapy. This helps aiding the clinical decision making process and the implementation of personalized treatment protocols for different patients according to their disease extent and potential for response to chemotherapeutics.
Supervisor: Hanna, George ; Keun, Hector Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral