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Title: The presence and origins of chromosomal instability in Barrett's oesophagus
Author: Doak, S. H.
Awarding Body: University of Wales Swansea
Current Institution: Swansea University
Date of Award: 2004
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Barrett’s oesophagus is a pre-malignant lesion characterised by the conversion of the squamous cell epithelium to a columnar cell mucosa. It is an ideal model for research into the genetic basis of oesophageal tumourigenesis, as it progresses to an adenocarcinoma through a series of histologically identifiable stages and is easily accessible. The purpose of this investigation was to contribute to the molecular characterisation of the Barrett’s progression model. Both molecular and cytogenetic methodologies were therefore utilised to examine the potential underlying mechanisms and subsequent consequences of any events detected. To facilitate initial cytogenetic investigations an assay that coupled brush cytology sampling and interphase FISH was developed. The technique was subsequently implemented to determine at which histological stage certain chromosomal alterations first arose. Chromosomal instability was detected well before dysplasia, with chromosome 4 & 8 hyperploidy representing the earliest and most common alterations identified. Both aberrations were widespread at all pre-malignant stages, but chromosome 4 hyperploidy was most predominant. FISH probes were consequently designed and developed to confirm the whole chromosome was amplified. The ensuing studies were designed to identify potential causative mechanisms responsible for the chromosomal instability identified. The p53 status in oesophageal adenocarcinoma was characterised at the gene sequence, chromosomal, mRNA and protein levels, then its association with aneuploidy was assessed. P53 mutations and deletions were not frequent events, but 83% of tumours demonstrated protein accumulation. No correlation between p53 alterations and aneuploidy was detected. The roles of centrosomal and mitotic spindle checkpoint aberrations in the induction of aneuploidy were then investigated. Centrosomal anomalies very rarely arose and although genes involved in the mitotic checkpoint demonstrated transcriptional alterations, they did not correlate with chromosomal instability. However, expression levels of the HSP27 and MAD2 genes demonstrated potential as predictive tools for the aggressiveness of oesophageal adenocarcinomas.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available