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Title: Identification of unique genetic and epigenetic signatures in myeloproliferative neoplasms using microarray and next generation sequencing : association with MPN-related mutations and clinical phenotypes
Author: Wong, Chieh Lee
ISNI:       0000 0004 6422 7204
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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The past decade has witnessed significant progress in the understanding of the molecular pathogenesis of myeloproliferative neoplasms (MPN). Mutations in a large number of genes have now been implicated in the pathogenesis of MPN but their relative importance, the mechanisms by which they cause different cells to predominate and differentiate into the separate MPN syndromes and their implications for prognosis remain unknown. I hypothesized that other genes and epigenetic mechanisms may contribute to the pathogenesis of the different disease subtypes at a cell-type specific level. This study focused on four areas: (1) Clinical phenotype - The demographic and clinical landscape of MPN in Malaysia showed that MPN is predominantly found in older Malay men. Compared to other studies, there is a higher incidence of JAK2 V617F positivity, with a more severe clinical phenotype and complications. (2) MPN panel - JAK2 V617F is the commonest somatic driver mutation detected in MPN patients using this 26-gene MPN targeted sequencing panel. The highest allelic frequencies were found in polymorphonuclear (PMN) and mononuclear cells (MNC). Several novel variants were found. Primary myelofibrosis patients who harbor the JAK2 V617F in combination with ASXL1, DNMT3A, RUNX1, TET2 and U2AF1 putatively pathogenic variants were found to have more severe clinical phenotypes and poor prognosis. (3) Gene Expression and (4) DNA methylation - Using microarray and next generation sequencing techniques, cell type-specific differentially expressed genes and differentially methylated CpG sites were found in PMN and MNC in the different disease subtypes. The lack of differential expression and methylation in T cells validated the approach and indicated they are not part of the neoplastic clone. The differentially expressed genes and differentially methylated CpG sites with associated genes are candidate loci to explain the pathogenesis of MPN and its different forms. These loci also represent targets for further investigation and disease-specific therapeutic targets.
Supervisor: Laffan, Mike Sponsor: Universiti Kebangsaan Malaysia ; Government of Malaysia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral