Colorectal cancer (CRC) is the one of the commonest causes of cancer and cancer related death worldwide. Its aetiology is linked to a number of reversible and irreversible genetic and environmental factors, including age, sex, genetics, smoking and diet. There has been a drive in recent years for non-invasive biomarkers for many malignant and non-malignant diseases across multiple medical specialties. One of the areas of interest is the detection of volatile organic compounds (VOCs) in various bodily substances by means such as mass spectrometry and electronic noses. CRC patients have been shown to be distinguishable from healthy controls using urinary VOC detection in several studies, including two published by the research group at UHCW and the University of Warwick. There has also been much interest in recent years into the role that the intestinal microbiome plays in health and disease in humans. The aim of this thesis was to characterise the urinary VOC and stool microbiome profiles of CRC patients, their spouses and first degree relatives. The aim being to determine whether the urinary VOC profiles could be distinguished using this technology and to try and better understand the underlying mechanism which lead to CRC carcinogenesis. The first degree relatives and spouses were selected as “common gene pool” and “shared environment” control groups respectively. This work was done using an LC-FAIMS-MS hybrid machine to detect urinary VOCs and 16s RNA sequencing using an Illumina Miseq platform. Comparisons were also made between pre-treatment and post-treatment CRC samples to try and determine if there was any change in either VOC or microbiome profiles after CRC treatment. The urinary VOC profiles of CRC subjects could be distinguished from both sets of healthy controls using a 5-fold cross validation and sparse logistics regression and Random Forrest statistical classifiers, achieving sensitivities of 63-69%, specificities of 64-69% and AUC 0.71-0.72. No statistically significant differences could be found in the urinary VOC profiles of pre-operative and post operative samples. Microbiome analysis revealed over 1300 operational taxonomic units (OTUs), with a similarity of >93% between the CRC samples and the control groups, with significantly different bacterial abundances identified in only 82 OTUs (6.2%), mainly Clostridiales bacteria. Pre-treatment and post-treatment sample analysis revealed differences of 17 (3%) and 22 (4%) OTUs at 3 and 6 months respectively, again principally clostridiales. This thesis provides further data on the microbiome composition in CRC. It also provides further proof of the utility of urinary VOCs, for the first time here using LC-FAIMS-MS technology, a variant of the previously utilised FAIMS technology, as a non-invasive biomarker for CRC.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:759660 |
| Date | January 2017 |
| Creators | McFarlane, Michael J. |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/111126/ |
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