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Title: Molecular analyses of malignant pleural mesothelioma
Author: Lo, Shir Kiong (Karl)
ISNI:       0000 0004 5994 3214
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Malignant pleural mesothelioma (MPM) is an aggressive cancer that is strongly associated with asbestos exposure. Majority of patients with MPM present with advanced disease and the treatment paradigm mainly involves palliative chemotherapy and best supportive care. The current chemotherapy options are limited and ineffective hence there is an urgent need to improve patient outcomes. This requires better understanding of the genetic alterations driving MPM to improve diagnostic, prognostic and therapeutic strategies. This research aims to gain further insights in the pathogenesis of MPM by exploring the tumour transcriptional and mutational profiles. We compared gene expression profiles of 25 MPM tumours and 5 non-malignant pleura. This revealed differentially expressed genes involved in cell migration, invasion, cell cycle and the immune system that contribute to the malignant phenotype of MPM. We then constructed MPM-associated co-expression networks using weighted gene correlation network analysis to identify clusters of highly correlated genes. These identified three distinct molecular subtypes of MPM associated with genes involved in WNT and TGF-β signalling pathways. Our results also revealed genes involved in cell cycle control especially the mitotic phase correlated significantly with poor prognosis. Through exome analysis of seven paired tumour/blood and 29 tumour samples, we identified frequent mutations in BAP1 and NF2. Additionally, the mutational profile of MPM is enriched with genes encoding FAK, MAPK and WNT signalling pathways. We also found mutations in several novel genes involved in chromatin remodelling other than BAP1 and SETD2 that may contribute to dysregulation of gene expression in MPM. In conclusion, MPM is a complex disease with heterogeneous molecular aberrations. By combining findings from both transcriptome and exome analyses, we identified alterations in genes involved in common signalling pathways such as FAK, WNT and MAPK. These may have important roles in driving MPM carcinogenesis with therapeutic implications and require further explorations.
Supervisor: Cookson, William C. ; Popat, Sanjay Sponsor: Royal Marsden Hospital ; Government of Brunei
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral