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Title: Investigation of dysfunctional aromatic amino acid metabolism in oesophago-gastric cancer and link to phenol production
Author: Wiggins, Thomas Henry
ISNI:       0000 0004 8499 3715
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Oesophago-gastric cancer is a significant health problem in the United Kingdom. Only 37.6% of patients can be treated with curative intent at the time of diagnosis. The development of non-invasive biomarkers aims to identify patients at early stages of the condition prior to disease spread. Phenol has been proposed as a potential marker of oesophago-gastric cancer in exhaled breath and urine. The nature of origin of this compound is unknown. The aim of this research was to investigate the link between aromatic amino acid metabolism and phenol production in oesophago-gastric cancer; the long term aim being to validate the use of phenol as a non-invasive marker of this disease. Dried blood spot samples were analysed using nano-electrospray ionisation mass spectrometry to identify intermediary metabolites of aromatic amino acid metabolism. Homogentisate was identified at reduced concentrations in oesophago-gastric cancer patients. These results led to a targeted investigation of enzymes regulating this pathway using quantitative PCR and immunohistochemistry. Homogentisate 1,2 dioxygenase was found to be downregulated in oesophageal cancer tissues. To investigate phenol production gastric content samples were analysed using gas-chromatography mass spectrometry. Phenol was consistently identified within gastric content samples, and addition of isotope labelled tyrosine indicated that phenol was produced from this aromatic amino acid in gastric juice. Bacterial sequencing identified the presence of phenol producing bacteria within the stomach. Phenol concentrations were significantly increased in the plasma of these patients, providing a transport mechanism for phenol produced in the tumour environment to be excreted by the lungs or kidneys. Urinary analysis also revealed increased concentrations of phenol relative to controls. This work has indicated that the gastric microbiome may be responsible for conversion of tyrosine to phenol in oesophago-gastric cancer. The underlying mechanism responsible for aromatic amino acid dysfunction has also been identified. By demonstrating the biological mechanism responsible for phenol production this project has validated the use of this compound as a non-invasive marker of this disease in exhaled breath or urine. These findings will help to introduce the clinical use of phenol as a non-invasive marker for oesophago-gastric cancer risk stratification, thereby increasing the proportion of patients diagnosed at early stages of disease and improving overall survival.
Supervisor: Hanna, George ; Takats, Zoltan Sponsor: Royal College of Surgeons of England
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral