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Title: Genetic aberrations in patients with leukaemia and their impact on prognosis
Author: Kreil, S.
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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Leukaemia is believed to arise through a multistep accumulation of genetic changes that result in deregulation of cell growth, differentiation, and programmed cell death. Many of these acquired changes are important indicators of prognosis and increasingly are being used to direct therapy. Inherited genetic factors may also influence the course of disease and response to treatment. The work of this thesis focuses on (i) the prognostic effect of derivative chromosome 9 deletions associated with the BCR-ABLl fusion gene in chronic myeloid leukaemia (CML) and (ii) the frequency of acquired point mutations in myeloid and lymphoid disorders, and (iii) a single nucleotide polymorphism that is associated with ST AT3 expression and response of CML to therapy with interferon alpha. Deletions within the derivative chromosome 9, or der(9), of the translocation t(9;22)(q34;qll), are seen in approximately 10-15 % of CML patients and have been associated with a poor prognosis, however no studies have been performed in the context of a randomised clinical trial. A DNA-based deletion screen was developed and 339 chronic phase patients treated with IFN as first line therapy in three controlled German studies with a median observation time of seven years were investigated. Deletions were detected in pre-treatment DNA samples of 59 out of 339 patients in total (17 %). Of these, 21 spanned the ABLl-BCR junction and 38 were centromeric only (n=20) or telomeric only (n=18) of the breakpoint. There was no significant difference in overall survival between deleted and nondeleted patients. Patients with breakpoint-spanning deletions had poorer survival compared to patients without deletions (4.7 versus 7.8 years; P=0.003) but this was not significant when censored at allogeneic stem cell transplantation (n=129) or imatinib (n=62) treatment in first chronic phase (P=0.078). Unexpectedly, deletions that did not span the breakpoint were associated with improved survival compared to cases without deletions (P=O.OOl). Multiple Cox regression analysis indicated that deletion status (P=0.007), age (P=0.018) and spleen enlargement (P
Supervisor: Cross, Nicholas ; Chase, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH426 Genetics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)