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This dissertation, Immunoglobulin Gene Translocations in Gastric Lymphoma by Bon-ham, Yip, 葉邦瀚, 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 Immunoglobulin Gene Translocations in Gastric Lymphoma submitted by Yip Bon Ham for the degree of Master of Philosophy at The University of Hong Kong in August, 2006 Primary gastric B-cell lymphoma (GL) is the most common type of extranodal non-Hodgkin's lymphoma and can be classified into extra-nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), diffuse large B-cell lymphoma (DLBCL) and composite DLBCL with residual MALT lymphoma (DLCLML). In Hong Kong Chinese, gastric DLBCL is the more prevalent subtype whereas gastric MALT lymphoma is more common in Caucasians. In order to better understand the molecular pathogenesis of GL in Hong Kong Chinese, this thesis aims to (1) identify novel translocation partners of IGH, IGL and IGK locus, (2) analyze p53 gene mutations, and (3) investigates the inverse correlation between BCL6 and tumor suppressor genes p53 and p21 expression in GL. To identify novel IG translocation partners, long distance inverse-PCR was used on 34 cases of GL for cloning the IGH translocation breakpoints at IGHJ, IGHS, Sγ and Sα regions. To clone translocations targeted to the IGK J and IGL J-C segments, a novel inverse-PCR method was developed. Significantly, three novel translocations t(14;20)(q32;q12), t(2;14)(q23;q32) and t(17;22)(q25;q11.2) were identified, involving the IGH J6 and IGH Sγ3, and IGL C4 respectively. The frequency of each of the novel translocation was next determined by direct PCR on 58 GL cases, 8 non-gastric extra-nodal lymphomas and 27 nodal DLBCL cases. The t(14;20)(q32;q12) was found in 2/58 (3.4%) of GL cases, 1/8 (12.5%) non-gastric extranodal lymphomas and 1/27 (3.7%) of nodal DLBCL cases. The t(2;14)(q23;q32) and t(17;22)(q25;q11.2) were both found only in GL cases (3/58; 5.2%). All these DLBCL translocation positive cases were of germinal centre B-cell (GCB) like phenotype. The transcribed loci Hs.147834 and Hs.580557 were the adjacent gene candidates of the two translocations; their expression might be altered due to the long-distance effect of IGH locus. The t(17;22)(q25;q11.2) resulted in the formation of RAPTOR/IGL fusion gene which may disrupt the mTOR pathway resulting in the activation of the Akt pathway. To investigate the role of p53 in GL, mutational analysis of the entire coding region of p53 and the p53's BCL6-binding site (-272 and -1806) was performed. Among the 66 p53 missense mutations, 60.6% were targeted to the DNA-binding domain; R273H (7.5%) and R248Q (5.0%) were the two most common mutations. In addition, two novel -1806 region mutations within the BCL6 binding site of p53 were identified. Deletions at codon 258, 281 and 367, insertion between codon 261-262 and polymorphism at codon 72 were also identified. A direct correlation between the Pro72 variant and p53 gene's DNA-binding domain mutations (p=0.015) was demonstrated. To investigate the inverse correlation between BCL6 and tumor suppressor genes p53 and p21 expression in GL, immmunostaining for these proteins was performed. A significant inverse correlation between BCL6 and p21 expression in the DLBCL cases (p=0.029) was observed in GL, which is consistent with the recent findings on the indirect suppression of p21 expression by BCL6 protein via binding to Miz-1 in nodal DLBCL. However, in contrast to nodal DLBCL, a significant inverse correlation between BCL6 and p53 expr

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