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Type: Thesis
Title: Aberrant DNA methylation in oesophageal cancer and Barrett’s oesophagus.
Author: Smith, Eric
Issue Date: 2010
School/Discipline: School of Medicine
Abstract: Oesophageal cancer is the eighth most common cancer and the sixth most common cause of death from cancer worldwide. There are two main histological types of oesophageal cancer: squamous cell carcinoma (ESCC), adenocarcinoma (EAC). In the developing world the major histological type is ESCC, whilst in the developed world EAC is increasing rapidly in incidence and is now the major type. Both histological types have a similarly poor prognosis, with a high morbidity and mortality. Barrett’s oesophagus (BE) is considered a precursor to EAC. It is found in up to 1.5% of the general population, and in up to 12% of patients who are investigated for chronic reflux symptoms. Approximately 0.5 to 1% of patients with BE will develop EAC each year, and patients with BE have 30- to 125-fold increased risk of EAC compared to the general population. Gastro-oesophageal reflux is the major risk factor for the development of BE and EAC, and medical and surgical anti-reflux therapies are available to relieve symptoms of the reflux and prevent reflux-related complications, although it is not certain if they will prevent the development of cancer. The development of oesophageal cancer is associated with an accumulation of genetic abnormalities, with some reports suggesting a stepwise progression of genetic changes involving the up-regulation and down-regulation of critical genes. Methylation of cytosine residues in CpG dinucleotides of the promoter regions of genes, DNA methylation, is a genomic change associated with silencing of gene expression. In the studies described in this thesis I have developed a simple quantitative method to assess DNA methylation using the melt data obtained following amplification of bisulphite modified DNA. I identified eight genes (BNIP3, FBN2, ID4, MLF1, PRDM2, RBP4, RARRES1, TFAP2C) that had been reported methylated in other cancers, but not before in BE or EAC, and four genes (CLDN6, DCBLD2, FNBP1 and MGC16824) that had not previously been reported as methylated in any cancer. I have shown that in non-dysplastic (metaplastic) BE, methylation of APC, ID4, MGMT, RBP1, SFRP1, TIMP3 and TMEFF2 (but not RUNX3 or CDKN2A) occurs as frequently in BE as EAC, suggesting that BE is more like cancer than normal squamous mucosa. I have used DNA methylation as a surrogate measure of the efficacy of fundoplication and proton pump inhibitor (PPI) treatment for BE. Five or more years after fundoplication there was a significant regression of BE and a reduction in the number of methylated genes in the remaining BE. In contrast, although high-dose PPI for six months significantly reduced inflammation and epithelial cell proliferation, it did not alter methylation. The reduction in methylation may be associated with a decreased risk for the development of dysplasia and adenocarcinoma. Finally, I have suggested extensions to the work published in this thesis. Further understanding of which genes are methylated in BE, EAC and ESCC, the mechanisms responsible for this aberrant methylation, and the function of the genes, would improve our insight into the underlying biology of oesophageal diseases, and potentially lead to new biomarkers or treatment options.
Advisor: Drew, Paul Anthony
Jamieson, Glyn Garfield
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2010
Keywords: DNA methylation; oesophageal cancer; Barrett's oesophagus
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
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