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This dissertation, BRAF Mutation and Aberrant Methylation of Gene Promoters in the Pathogenesis of Gastrointestinal Tract Adenocarcinoma by Wei, Zhao, 趙煒, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled BRAF mutation and aberrant methylation of gene promoters in the pathogenesis of gastrointestinal tract adenocarcinomas Submitted by ZHAO WEI for the degree of Doctor of Philosophy at the University of Hong Kong in February 2006 Carcinomas of the stomach and colon are two of the most common cancer types worldwide. They share some common phenotypic and molecular genetic pathways of tumour development. We examined for oncogenic mutations in members of the RAS/RAF/MEK/ERK/MAPKinase pathway in these two cancer types or their precursor lesions, so as to fill the current gaps of knowledge regarding the role of this pathway in their tumourigenic processes. We also looked for new genes that are putative TSG and down-regulated by aberrant promoter methylation in gastric cancer (GC). The RAS/RAF/MEK/ERK/MAPKinase pathway mediates cellular responses to growth signals. Whilst oncogenic mutation of KRAS is common in diverse human cancer types, recent studies have discovered the presence of oncogenic BRAF mutation in a small proportion of colorectal cancers (CRC), especially frequent in those with microsatellite instability (MSI). We examined for II the incidence of KRAS and BRAF mutations in 94 GCs and studied their possible relationship with MSI. Eight (8.5%) cases showed KRAS mutation and none had BRAF mutation. The low incidence of KRAS and BRAF mutation in GC suggested that either this pathway is rarely altered in gastric carcinogenesis, or alternatively other yet unknown members in this pathway are involved. Whilst the incidence of BRAF mutation in CRCs and adenomas are known, there is no data available regarding its occurrence in serrated polyps. The latter encompass a morphological spectrum including hyperplastic polyp (HP), admixed hyperplastic polyp/adenoma (HP/AD) and serrated adenoma (SA), that constitutes an alternative carcinogenic pathway through the HP-SA-carcinoma sequence. We have studied a large series of serrated polyps for BRAF and KRAS mutations, and found a high incidence of BRAF mutation in them (36% for HPs, 20% for HP/ADs, and 100% for SAs). 90% of the serrated polyps showing dysplasia had mutations in either BRAF or KRAS, significantly higher than those without dysplasia (54%) (p=0.014). Our data highlight the important role of activation of the RAS/RAF/MEK/ERK/MAPKinase pathway in the initiation and progression of serrated neoplasms. Aberrant methylation in the promoter CpG islands of TSGs could lead to their transcriptional silencing and contribute to cancer development. Based on gene expression profiling data, we identified genes that are down-regulated in GCs, and systematically screen for the presence of methylation in their gene promoters, using 20 GC cell lines and 90 patient GC samples. Nine genes were III studied initially, in which five showed promoter methylation that correlated with down-regulated gene expression in GC cell lines. In depth in vitro studies for two genes confirmed their re-expression by 5-Aza-dC treatment accompanied by de-methylation of their promoter. Moreover, aberrant methylation was detected in a proportion of GC tissue but to a much lesser extent in non-tumour gastric mucosae. A review of the known functions of these two genes showed their involvement in actin cytoskeleton organisation, sonic-hedgehog signaling or DNA methyl-group metabolism, processes that are intric

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