Peng, Huaizheng; (1998) The molecular basis of high-grade transformation of B cell lymphoma of mucosa associated lymphoid tissue (MALT). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Low-grade B cell MALT lymphomas are closely associated with chronic inflammation including autoimmune disorders, such as Hashimoto's disease in the thyroid and bacterial infection, such as Helicobacter pylori related gastritis in the stomach. They are clinically indolent, but can transform into high-grade tumours at a late stage. In this study, molecular biological methods have been used to investigate the molecular basis of this high-grade transformation. To establish a clonal link between low and high-grade MALT lymphomas, clone-specific rearrangements of immunoglobuiinheavy chain (IgH) gene were determined in coexisting low and high-grade lesions, identical IgH rearrangements demonstrated in both lesions indicated that high-grade MALT lymphomas were directly derived from low-grade tumours. H pylori strains containing the CagA gene are known to be more virulent than those without the gene. Using a sensitive PCR based assay, a higher frequency of infection by CagA+ bacteria was observed in high-grade gastric lymphoma than in low-grade lymphoma and gastritis controls. This suggests that high-grade transformation may be more likely to occur following infection by CagA+ H pylori. More than half of the MALT lymphomas studied in this project were shown to possess an RER+ phenotype (an indicator of genetic instability), suggesting that genetic instability is a common feature of the tumour. Frequent somatic mutations in the c-myc regulatory regions were also observed, indicating that these mutations may be important in the development of MALT lymphoma. P53 abnormalities (point mutation, loss of heterozygosity and over-expression) were found in a significant proportion of MALT lymphomas, with a higher incidence and more complex patterns in high-grade than low-grade tumours, indicating a possible role of these abnormalities in high-grade transformation. An interrelationship between p53 abnormalities and RER+ phenotype was also demonstrated. The results presented here show that, like other tumours, the development of MALT lymphomas is a multistage process. High incidence of genetic instability may be associated with chronic inflammation, which provides a basis for accumulation of genetic abnormalities leading to evolution of MALT lymphomas. Further alterations of vital genes, such as c-myc and p53 may result in progression or high-grade transformation of the tumour.

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