An investigation of novel biomarkers of gastric mucosal preneoplasia
(i) Novel biomarkers of gastric preneoplasia following infection with Helicobacter pylori Despite steady decline in incidence, gastric cancer remains a major global cause of morbidity and mortality and is responsible for over 700,000 deaths worldwide per annum. The commonest form arises following infection with the bacterium Helicobacter pylori. For reasons which remain poorly understood, a small proportion of infected individuals develop gastric epithelial remodelling which follows a well-defined sequence of changes culminating in cancer development. Our group and others have described the role of various gastric mucosal proteins in carcinogenesis following H. pylori infection. We hypothesised that these proteins might be upregulated in gastric preneoplasia and might in turn be used as biomarkers of the same. We recruited patients attending hospital for diagnostic upper gastrointestinal endoscopy. Gastric biopsies were taken to determine the presence and extent of preneoplastic lesions by histology; H. pylori status; and the abundance of mRNA for putative biomarkers by real-time polymerase chain reaction. Blood was drawn to determine the serum concentrations of H. pylori IgG antibodies, fasting gastrin and pepsinogens 1 and 2. Genomic DNA was extracted from blood samples. For each subject, we performed genotyping for nine single nucleotide polymorphisms in the MMP-7 gene to determine whether these polymorphisms might increase the expression of mucosal MMP-7 or increase the risk of developing gastric preneoplasia. In our study population, the ratio of pepsinogens 1 and 2 (PG1/2 ratio) performed well as a diagnostic test for gastric mucosal preneoplasia. In combination with fasting serum gastrin concentration and H. pylori serology, the diagnostic accuracy was improved suggesting a role for these markers in clinical practice. We have demonstrated that the gene transcript abundance of one mucosal protein – matrix metalloproteinase-7 (MMP-7) – was significantly increased in the presence of gastric preneoplasia. This effect was greater for disease phenotypes associated with higher cancer risk. These novel findings confirm the increased expression of MMP-7 in gastric epithilial preneoplasia and offer insight into areas of development for the future including the use of MMP-7 as a noninvasive biomarker of gastric preneoplasia. We also found that gastric preneoplasia was significantly more common in minor allele homozygotes for SNP rs17352054 than for major allele homozygotes and that carriage of the minor allele of SNP rs11225297 is associated with gastric preneoplasia amongst H. pylori seropositive individuals. We have also shown a significant influence on mucosal MMP-7 relative mRNA abundance of SNP genotypes for six of the polymorphisms examined.
Moore, Andrew (2015) An investigation of novel biomarkers of gastric mucosal preneoplasia PhD thesis, University of Liverpool.
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