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Title: Alterations of tumour protein 53 (TP53) pathways in diffuse large B-cell lymphomas
Author: Magdi Abdel-Azim, Dalia
ISNI:       0000 0004 2720 6500
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2009
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Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It has heterogeneous clinical features and varies markedly in response to treatment and in prognosis. Although the clinical variables widely used in clinical practice may be useful indicators in defining the underlying biological heterogeneity of DLCL, a search for molecular expression, such as TP53, would improve the prognostic predict ability and current understanding of the clinical behaviour of DLBCL. Seventy-two cases of DLBCL were assessed by immunohistochemistry using primary antibodies for TP53, p21, HDM2, Phospho-TP53, Bcl-2, Bcl-6 and MIB-1. There was a significant positive correlation between high proliferation index and TP53, phopho-TP53 and Bcl-6 expressions (p<0.005), while a significant negative correlation was found with Bcl-2 expression (p<0.005). Bcl-2 expression showed an inverse correlation with TP53, phospho-TP53, Bcl-6 (p<0.005). TP53 assessed using the DO-1 antibody showed a significant correlation with phopho-TP53 (p<0.005). p21 showed a similar correlation with HDM2 (p<0.005). TP53 mutations were assessed using PCR-SSCP analysis in 64 cases of DLBCL. The frequency of TP53 mutations in this study was 18.75%. Exon 7 harboured most mutations (30%). There was a significant correlation between low expression of TP53 and phospho- p53 assessed by immunohistochemistry and the presence of WT-p53, but not vice versa. Also, a significant correlation was found between missense TP53 mutations and TP53+/p21- phenotype (p<0.005). High proliferation index correlated with TP53 mutations (p<0.005). There was a strong association of the presence of TP53 mutations and low level of miR-34a (p<0.05). A strong correlation between miR-34a expression levels and TP53, p21 and HDM2 (p <0.05). In conclusion, although 80% of DLBCL cases posses WT-p53 gene , not of them are fully functional and they show phenotypic variabilty in their TP53 activity. Other mechanisms for inactivating TP53 must be responsible, such as alterations of the downstream or upstream regulators or targets that will mimic a TP53 aberration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available