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dc.contributor.authorÓ Riain, Ciarán Liam
dc.date.accessioned2011-07-12T15:39:03Z
dc.date.available2011-07-12T15:39:03Z
dc.date.issued2010
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/1318
dc.descriptionPhDen_US
dc.description.abstractFollicular Lymphoma (FL) is a common B cell Non-Hodgkin Lymphoma with a median survival of 8-10 years. Patients frequently undergo transformation to a more aggressive lymphoma and this is associated with drastically reduced survival. The hallmark of FL is the t(14;18) translocation yet this alone is insufficient for lymphomagenesis. While a number of secondary genetic changes have been described, epigenetic studies have lagged behind. Epigenetics refers to mechanisms that alter gene expression without a change in the primary DNA sequence. DNA methylation was quantitatively profiled at 1505 CpG loci in 164 untreated FL as well as 10 pairs of pre- and post-transformation samples and 24 benign haematopoietic controls. Tumour-specific methylation occurred in >100 genes, preferentially occurring within CpG rich areas known as CpG islands and in genes marked by a repressive histone modification in embryonic stem (ES) cells, trimethylated Lysine 27 of Histone H3 (H3K27Me3). Significant inverse correlation with gene expression was identified for a small number of genes. Significant changes in methylation were not seen in FL samples upon transformation. These findings suggested that widespread DNA methylation occurred as an early 'pre-programmed' event in lymphomagenesis rather than being due to silencing of individual tumour suppressor genes. Methylation profiling of a subset of these samples at >27,000 CpG loci revealed aberrant methylation in FL in >700 CpG islands. These hypermethylated genes were enriched for high-density CpG promoters and for a key set of genes with developmental function which were marked by both repressive (H3K27Me3) and activating (H3K4Me3) marks in ES cells. Examination of H3K27me3 expression by immunohistochemistry in pre- and post-transformation biopsy samples showed wide variation in expression. Furthermore, mutations were identified in the histone methylase EZH2 that catalyses H3K27Me3, in 7 of 20 patients. We can conclude therefore that deregulation of DNA and histone methylation are critical inter-related events for FL pathogenesis.
dc.language.isoenen_US
dc.subjectMedicineen_US
dc.titleDNA methylation in follicular lymphomaen_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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    Theses Awarded by Queen Mary University of London

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