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This dissertation, Novel IGH Translocations in Gastric Non-Hodgkin's B-cell Lymphoma by Xiaotong, Hu, 胡曉彤, 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 NOVEL IGH TRANSLOCATIONS IN GASTRIC NON- HODGKIN'S B-CELL LYMPHOMA submitted by Hu Xiaotong for the degree of Doctor of Philosophy at the University of Hong Kong in April 2007 Gastric B-cell lymphoma is the most common type of extranodal non- Hodgkin's lymphoma (NHL) in Hong Kong Chinese. In the mature B-cell malignancies, and notably in the B-cell non-Hodgkin's lymphomas (B-NHLs), the most common genetic features are the chromosomal translocations in which segments of other chromosomes become juxtaposed with the IGH locus at band 14q32. Rearrangements of specific oncogenes with the IGH gene are found in certain subtypes of lymphomas showing distinct pathologic, immunophenotypic, and clinical features. Information about these specific IGH translocations is of great importance for the clinical diagnosis and therapeutic management of B-cell lymphomas. In this study, long-distance inverse PCR (LDI-PCR) was employed to clone novel IGH translocation partner genes and the role of these genes in the pathogenesis of lymphoma was also explored. Translocations were studied in 50 primary gastric B-cell NHL (GL) cases, with 8 non-gastric extranodal (ENL) and 26 nodal lymphoma cases (NL) included for comparison. Firstly CD44 at chromosome 11p13 was identified as a novel translocation partner gene of IGH in primary GL. Our results showed that CD44 expression was regulated by different mechanisms operating simultaneously in GL: chromosomal translocation and Helicobacter pylori (H. pylori) infection in cases with strong CD44 expression and gene silencing by promoter hypermethylation in cases lacking CD44. Strong CD44 expression was associated with poor prognosis in GL and NL, and the cases with unmethylated CD44 were positively correlated with high stage. In this study, IGH/BCL2 translocation was also found to be a recurrent chromosomal translocation in GL cases for the first time. Our results suggested that IGH/BCL2 translocation, BCL2 promoter hypermethylation and BCL2 somatic mutations operated simultaneously in gastric lymphoma cases. BCL2 somatic mutations may play an important role in GL transformation and progression and BCL2 P1 promoter region methylated status could predict good prognosis in non- GCB group GL cases. Moreover PRKCBP1 was also identified as a recurrent novel translocation partner gene of IGH in gastric lymphoma. Time constraints limited my studies of this translocation, but based on the evidence from recently available PRKCBP1 related papers, IGH/PRKCBP1 translocation and the PRKCBP1 gene may play an important role in the pathogenesis of lymphoma. Lastly, CD44 and BCL2 expression and their promoter methylation status in a panel of B-cell lineage tumor cell lines corresponding to different stages of B-cell development was analysed. Our results showed for the first time that CD44 and BCL2 were differentially expressed during B cell development through a methylation or demethylation control mechanism. In conclusion, the results described in this thesis not only provide significant novel findings on the genetic and epigenetic events underlying gastric lymphomagenesis, but also give clues on the clinical diagnosis, prognosis and therapeutic management of gastric lymphoma. DOI: 10.5353/th_b3868809 Subjects: Chromosome abnormalityTranslocation (Genetics)ImmunoglobulinsGastrointestinal system - Cancer - Genet

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